Substituted pyrrolidines as G-protein coupled receptor 43 agonists

ABSTRACT

The present invention is directed to novel intermediates of the formula E: 
                         
which are useful in the synthesis of agonists of g-protein coupled receptor 43 for treating and/or preventing metabolic diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a Division of U.S. patent application Ser. No. 16/013,281 filed on Jun. 20, 2018, which Application is a Divisional of U.S. patent application Ser. No. 15/624,290 filed on Jun. 15, 2017, which Application is a Divisional of U.S. patent application Ser. No. 13/526,337 filed on Jun. 18, 2012, which Application is a Continuation of International PCT Patent Application No. PCT/EP2010/070040 filed on Dec. 17, 2010, which Application claims the benefit of priority to U.S. Provisional Patent Application No. 61/376,013 filed on Aug. 23, 2010 and U.S. Provisional Patent Application No. 61/373,370 filed on Aug. 13, 2010 and European Patent Application No. 09306270.1 filed on Dec. 18, 2009. The entire contents of these applications are incorporated herein by reference in their entirety.

The present invention relates to novel compounds including their pharmaceutically acceptable salts, solvates and prodrugs, which are agonists or partial agonists of G-protein coupled receptor 43 (GPR43) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of Type 2 diabetes mellitus and conditions that are often associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

BACKGROUND OF THE INVENTION

Under normal conditions, Free Fatty Acids (FFAs) are implicated in numerous physiological processes by serving as fuel in various metabolic pathways and/or acting as signaling molecules in different tissues such as the heart, liver, skeletal muscle, adipocytes and the pancreas (Newsholme et al., Biochem. J., 80 pp 655-662, 1961; Prentki et al., Endocrine Reviews, PubMed print ahead, 2008). Among FFAs, the short-chain fatty acids (SCFAs, carbon length C2-C6) are generated during anaerobic bacterial fermentation of fiber in the gut (Sellin et al., News. Physiol. Sci., 14, pp 58-64, 1999). Long-chain fatty acids (LCFAs, carbon length C14-C24) are products of dietary intake from adipose tissues and liver (McArthur et al., J. Lipid. Res., 40, pp 1371-1383, 1999).

Obesity is an increasing, worldwide public health problem associated with devastating pathologies such as type 2 diabetes (T2D) and dyslipidemia (Wild et al., Diabetes Care 27, pp 1047-1053, 2004). Dyslipidemia is characterized by high levels of triglycerides and/or LDL (bad cholesterol) or low levels of HDL (good cholesterol). Dyslipidemia is a key independent risk factor for cardiovascular diseases. It has long been suggested that FFAs are implicated in the regulation and/or genesis of these diseases (Fraze et al., J. Clin. Endocrinol. Metab., 61, pp 807-811, 1985). It is well established that regular intake of dietary fiber has several beneficial metabolic effects such as lowering of plasma cholesterol and triglyceride levels (Anderson et al., J. Am. Coll. Nutr., 23, pp 5-17, 2004). Specifically, dietary fiber has been shown to increase endogenous levels of SCFAs, leading to the suppression of cholesterol synthesis and improvement in glucose tolerance in rat (Berggren et al., Br. J. Nutr., 76, pp 287-294, 1996), as well as the reduction of hyperglycemia in a diabetic mice model (Sakakibara et al., Biochem. Biophys. Res. Corn., 344, pp 597-604, 2006).

Drug therapies are available to address both T2D and dyslipidemia. Specifically, statins, fibrates and nicotinic acid or combinations thereof are often considered as a first line therapy in dyslipidemia whereas metformin, sulphonylureas and thiazolidinediones are three, widely-used classes of oral anti-diabetic drugs (Tenenbaum et al., Cardiovascular Diabetology, 5, pp 20-23, 2006). Although theses therapies are widespread in their use, the common appearance of adverse effects or lack of efficacy after long-term use causes concern. Moreover, the growing patient population suffering from T2D, dyslipidemia and associated metabolic diseases creates a demand for new entrants into this therapeutic market.

GPR43 (also named FFA2R) belongs to a subfamily of G-Protein-Coupled Receptors (GPCRs), including GPR40 and GPR41 that have been identified as receptor for FFAs (Le Poul et al., J. Biol Chem. 278, 25481-489, 2003; Covington et al., Biochemical Society transaction 34, 770-773, 2006). The 3 family members share 30 to 40% sequence identity with specificity toward different fatty acids carbon chain lengths, with SCFAs (short chain fatty acids: six carbons molecules or shorter) activating GPR41 and GPR43; and medium and long chain fatty acids (MCFA, LCFA) activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 11 661-671, 2007). C2 acetate and C3 propionate are the most potent activators of GPR43. GPR43 is mainly coupled with Gq-proteins, with some evidence for its possible coupling with Gi/o pathways as well.

GPR43 is strongly expressed in adipocytes. Also there is evidence suggesting that GPR43 is overexpressed in pancreatic β-cells in prediabetic states as shown in WO2006/036688A2. Recent papers confirmed the GPR43 expression in pancreatic islets (Ahrén, Nature Reviews, 8 pp 396-385; 2009; Regard et al., J; Clin. Invst., 117 pp 4034-4043, 2007). In adipocyte cells, GPR43 is induced during the differentiation process and increased during the high fat feeding in rodents, suggesting that GPR43 may affect adipocyte functions (Hong et al., Endocrinology, 146 pp 5092-5099, 2005). Indeed, it has been reported that acetate and propionate may stimulate adipogenesis via GPR43. In addition siRNA results hinted that acetate and propionate may inhibit lipolysis in adipocytes via GPR43 activation (Hong et al., Endocrinology, 146 pp 5092-5099, 2005). It is interesting to note that the effect of acetate on reducing plasma free fatty acids level has been documented in humans (Suokas et al., Alcoholism, clinical and experimental research, 12 pp 52-58, 1988; Laurent et al., European journal of clinical nutrition, 49 pp 484-491, 1995). In addition, it has been shown that (i) adipocytes treated with GPR43 endogenous SCFA ligands exhibit a reduction in lipolytic activity and such inhibition of lypolysis is the result of GPR43 activation and (ii) GPR43 activation by acetate results in the reduction of plasma free fatty acids level in vivo (Ge et al., Endocrinology, 149 pp 4519-26, 2008). Recently two GPR43 positive allosteric modulator molecules have been shown able to inhibit the lipolysis in adipocytes similarly to that of GPR43 endogenous SCFA ligands (Lee et al., Mol Pharmacol, 74(6) pp 1599-1609, 2008). Such results suggest a potential role of GPR43 in regulating plasma lipid profiles and aspects of metabolic syndrome.

On this basis, new agonists or partial agonists of GPR43 may be of therapeutic value for T2D mellitus and conditions that are associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

SUMMARY OF THE INVENTION

The invention encompasses compounds of general Formula I, their pharmaceutically acceptable salts, solvates and prodrugs as well as methods of use of such compounds or compositions comprising such compounds as modulators of GPR43 activity.

In a general aspect, the invention provides compounds of general formula I:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar¹ is a 5- to 6-membered aryl or heteroaryl group, 3- to 8-membered     cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a     linear or branched C₃-C₆ alkyl group, each of which being optionally     substituted by one or more group(s) selected from halo, cyano,     alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,     alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl,     aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy,     haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino,     alkylamino, aminoalkyl, carboxy, alkoxycarbonyl,     cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl,     heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy,     heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy,     arylalkyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, heterocyclylcarbonylamino     arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl,     carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     hcteroarylsulfonylamino, haloalkylsulfonylamino, or two substituents     form an alkylenedioxy group or a haloalkylenedioxy group, or two     substituents form a cycloalkyl or heterocycloalkyl moiety together     with the cycloalkyl or heterocycloalkyl group they are attached to,     or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl     group may be one or more cycloalkyl, aryl, heterocyclyl or     heteroaryl moiety, each of said substituents being optionally     substituted by one or more further substituents selected from halo,     cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,     heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy,     alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,     cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo; -   L¹ is a single bond, C₁-C₃ alkylene, C₃-C₆ cycloalkylene, C₂-C₃     alkenylene, C₂-C₃ alkynylene, each of which being optionally     substituted by one or more group(s) selected from halo, alkyl,     haloalkyl, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxyalkyl; -   R¹ is H, linear or branched C₁-C₄ alkyl; -   E is N, C—R⁵ where R⁵ is H, linear or branched C₁-C₄ alkyl; -   D is CO or D is where D is

linked to E either on the nitrogen or the carbonyl and R⁶ is H, alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl or alkoxyalkyl, and under the condition that E is C—R⁵;

-   L² is a single bond, C₁-C₄ alkylene, C₃-C₆ cycloalkylene, C₂-C₃     alkenylene, C₂-C₃ alkynylene each of which being optionally     substituted by one or more group(s) selected from halo, alkyl,     haloalkyl, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl or     alkoxyalkyl; -   Ar² is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C₂-C₆     alkyl group, each of which being optionally substituted by one or     more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl,     cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl,     heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,     benzoxazol-2-yl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy,     haloalkoxy, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy,     heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy,     arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl,     amino, alkylamino, aminoalkyl, arylcarbonyl, carboxy,     alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl,     aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy,     cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy,     heteroarylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, heterocyclylcarbonylamino     arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl,     carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, oxo or two     substituents form an alkylenedioxy group or a haloalkylenedioxy     group, or two substituents form a cycloalkyl or heterocycloalkyl     moiety together with the cycloalkyl or heterocyclyl group they are     attached to, or fused to the aryl, heteroaryl, cycloalkyl or     heterocyclyl group may be one or more cycloalkyl, aryl, heterocyclyl     or heteroaryl moiety, each of said substituents being optionally     substituted by one or more further substituents selected from halo,     cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl,     cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or     methyl group, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl,     alkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy,     aralkyloxy optionally substituted by a fluoro group, alkylamino,     carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy,     amino, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy,     carbamoylamino, alkylcarbamoylamino, carbamimidoyl,     hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino, oxo, aralkyl, heteroarylalkyl, alkoxyalkoxy,     alkoxyalkyl, and haloalkoxyalkyl. -   R² is H; -   L³ is a single bond, C₁-C₃ alkylene, C₃-C₆ cycloalkylene, C₂-C₃     alkenylene or C₂-C₃ alkynylene each of which being optionally     substituted by one or more group(s) selected from halo, alkyl,     haloalkyl, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxyalkyl; -   Z is selected from the group consisting of —COOR,

wherein R is H or linear or branched alkyl, aryl, acyloxyalkyl, dioxolene, R⁷ is H, methyl or ethyl, and R^(7′) is hydroxyl —SO₂CH₃, —SO₂cyclopropyl or —SO₂CF₃;

-   the bond represented by the dotted line is either absent or present; -   R³ is H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,     cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl,     heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,     hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy,     heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy,     arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy, acetyl,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoylalkyl,     carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl,     arylsulfonyl, heteroarylsulfonyl sulfamoyl, alkylsulfamoyl,     arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, heterocyclylsulfonylamino,     arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino,     or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl     group may be one or more cycloalkyl, aryl, heterocyclyl or     heteroaryl moiety, each of said substituents being optionally     substituted by one or more further substituents selected from halo,     cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl,     aryl, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy,     haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino or oxo; -   R^(3′) is H or C₁-C₄ alkyl, or R^(3′) is absent if the dotted line     is present; -   R⁴ is H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,     cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl,     aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy,     cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, amino     alkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,     heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy,     arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or fused to the     aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or     more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of     said substituents being optionally substituted by one or more     further substituents selected from halo, cyano, alkyl, hydroxyalkyl,     haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,     cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy,     cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino or oxo, or R⁴ forms together with R³ a     cyclopropane ring optionally substituted by one or more group     selected from halo, alkyl, haloalkyl, hydroxyl, alkoxy, or     haloalkoxy, under the condition that the dotted line is absent; -   R^(4′) is H, C₁-C₄ alkyl, or R^(4′) is absent if the dotted line is     present; -   under the condition that the compound of formula (I) is not -   (2S)-methyl 1-benzoyl-5-mesitylpyrrolidine-2-carboxylate, -   (2S)-methyl     1-benzoyl-5-(2,4,6-triethylphenyl)pyrrolidine-2-carboxylate, -   (2S,5S)-1-benzoyl-5-mesitylpyrrolidine-2-carboxylic acid, -   (2S)-methyl 1-benzoyl-5-propylpyrrolidine-2-carboxylate, -   (2S,5S)-methyl1-benzoyl-5-propylpyrrolidine-2-carboxylate, -   (2S,5R)-methyl 1-benzoyl-5-propylpyrrolidine-2-carboxylate, -   (2S,5R)-5-(tert-butyl)-1-(4-phenylbutanoyl)pyrrolidine-2-carboxylic     acid, -   (2S,5R)-methyl     5-(tert-butyl)-1-(4-phenylbutanoyl)pyrrolidine-2-carboxylate, -   (2R,5R)-1-(4-bromothiophene-2-carbonyl)-5-phenylpyrrolidine-2-carboxylic     acid, -   (2R,5S)-1-(3-bromo-2,6-dimethoxybenzoyl)-5-phenylpyrrolidine-2-carboxylic     acid, -   tert-butyl     2-[(2R,5S)-2-ethoxycarbonyl-5-phenyl-pyrrolidine-1-carbonyl]indoline-1-carboxylate, -   (2R,5S)-1-(1-tert-butoxycarbonylindoline-2-carbonyl)-5-phenyl-pyrrolidine-2-carboxylic     acid, -   1-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-(5R)-phenyl-pyrrolidine-(2S)-carboxylic     acid.

Advantageously, the compounds of the invention or pharmaceutically acceptable salts, solvates and prodrugs thereof are those described above in respect to formula (I) with the following provisos:

-   Ar² is not phthalazin-6-yl, pyrido[2,3-d]pyridazin-2-yl,     pyrido[2,3-d]pyridazin-3-yl, or pyrazino[2,3-d]pyridazin-2-yl;     and/or -   each of R³ and R⁴ is not a pyrimid-2-ylamino group substituted at     position 6 by a bicyclic heteroaryl group, if the bond represented     as a dotted line is absent; and/or -   R³ is not a mono substituted hydroxymethyl; and/or

The D-L²-Ar² moiety is not

wherein L is H or alkyl and L′ is selected from phenyl, naphthyl, indolyl, quinolyl, phenylamino.

In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.

The invention also relates to the use of the above compounds or their pharmaceutically acceptable salts, solvates and prodrugs as modulators of GPR43, preferably as agonists or partial agonists of GPR43.

The invention further provides methods of treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH) comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt or solvate of formula (I), to a patient in need thereof. Preferably the patient is a warm-blooded animal, more preferably a human.

The invention also provides the use of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as a medicament. Preferably, the medicament is used for the treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

In a preferred embodiment the disease is type II diabetes, a lipid disorder such as dyslipidemia, hypertension, obesity, or atherosclerosis and its sequelae.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the invention relates to compounds of formula I, as well as their pharmaceutically acceptable salts, solvates and prodrugs.

Preferred compounds of formula I and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein all the following descriptions are independently

-   the dotted line is absent and E is N; and/or -   L¹ is a single bond, preferably a single bond drawn as a solid     wedge; and/or -   L³ is a single bond, preferably a single bond drawn as a solid     wedge; and/or -   Z is selected from the group consisting of COOR wherein R is defined     as above in respect to formula I, preferably Z is COOH; and/or -   R³ is H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,     cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, 5-membered     heterocyclyl, heterocyclylalkyl, aryl, aralkyl, 5-membered     heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl,     haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino,     alkylamino, aminoalkyl, alkylcarbonyloxy, cycloalkylcarbonyloxy,     heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy,     arylalkyloxy, acetyl, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, heterocyclylcarbonylamino     arylcarbonylamino, heteroarlycarbonylamino, alkylcarbonylaminoalkyl,     carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl,     arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl,     arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, heterocyclylsulfonylamino,     arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino,     or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkyl     group may be one or more cycloalkyl, aryl, heterocyclyl or     heteroaryl moiety, each of said substituents being optionally     substituted by one or more further substituents selected from halo,     cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl,     aryl, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy,     haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl,     sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, haloalkylsulfonylamino or oxo, preferably     R³ is H, cyano, alkyl, haloalkyl, cycloalkylalkyl,     heterocyclylalkyl, aralkyl, heteroarylalkyl, alkoxyalkyl,     haloalkoxy, aminoalkyl, arylalkyloxy, acetyl,     haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoylalkyl,     sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl,     alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or a bicyclic ring     made by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl fused to     one cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of     said substituents being optionally substituted by one or more     further substituents selected from halo, cyano, alkyl, hydroxyalkyl,     haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,     cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy,     cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylamino     alkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl,     carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl,     alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino     or oxo, or R³ forms together with R⁴ a cyclopropane ring substituted     by one or more group selected from halo, haloalkyl, or haloalkoxy,     under the condition that the bond represented by the dotted line is     absent, more preferably R³ is H, cyano, alkyl, preferably methyl,     aralkyl, preferably benzyl, acetyl linked to the E containing ring     by bond drawn as a dotted wedge, alkoxyalkyl preferably     methoxymethyl, even more preferably R³ is H; and/or -   R⁴ is H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,     cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl,     aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy,     cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino,     aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl,     heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy,     arylcarbonyloxy, heteroarylcarbonyloxy, arylalkyloxy,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or fused to the     aryl, heteroaryl, cycloalkyl or heterocycloalkyl group may be one or     more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of     said substituents being optionally substituted by one or more     further substituents selected from halo, cyano, alkyl, hydroxyalkyl,     haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,     cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy,     cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino or oxo, or R⁴ forms together with R³ a     cyclopropane ring substituted by one or more haloalkyl, haloalkoxy,     under the condition that the dotted line is absent, preferably R⁴ is     H, methyl or cyano, more preferably R⁴ is H; and/or -   R^(3′) and R^(4′) are independently H or methyl, preferably R^(3′)     is H or methyl and R^(4′) is H, more preferably R^(3′) and R^(4′)     are both H; and/or -   D is CO and L² is a single bond; and/or -   Ar¹ is a 5- to 6-membered aryl or heteroaryl group, or a 3- to     6-membered cycloalkyl group, or a linear or branched C₃-C₆ alkyl     group, each of which being optionally substituted by one or more     group(s) selected from halo preferably bromo, chloro or fluoro,     cyano, C₁-C₄ alkyl preferably methyl, C₁-C₄ hydroxyalkyl, C₁-C₄     haloalkyl preferably CF₃ or CHF₂, cycloalkyl, cycloalkylalkyl,     heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably     phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, C₁-C₄ alkoxy     preferably methoxy, C₁-C₄ haloalkoxy preferably OCF₃ or OCHF₂, C₁-C₄     alkylamino, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, heterocyclylcarbonylamino     arylcarbonylamino, heteroarylcarbonylamino, C₁-C₄     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, C₁-C₄     alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl,     carbamoylamino, C₁-C₄ alkylcarbamoylamino, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl,     arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl,     arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, heterocyclylsulfonylamino,     arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino,     or two substituents form an alkylenedioxy group or a     haloalkylenedioxy group, or two substituents form a cycloalkyl or     heterocycloalkyl moiety together with the cycloalkyl group they are     attached to, or fused to the aryl, heteroaryl or cycloalkyl group     may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl     moiety, each of said substituents being optionally substituted by     one or more further substituents selected from halo, cyano, alkyl,     hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl,     hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino or oxo, more preferably Ar¹ is a phenyl,     pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl,     isobutyl or isopentyl group, each of said phenyl, pyridin-2-yl,     pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally     substituted by one or more group(s) selected from halo preferably     bromo, chloro or fluoro, cyano, C₁-C₄ alkyl preferably methyl, C₁-C₄     haloalkyl preferably CF₃ or CHF₂, cycloalkyl, aryl preferably     phenyl, heteroaryl, hydroxyl, C₁-C₄ alkoxy preferably methoxy, C₁-C₄     haloalkoxy preferably OCF₃ or OCHF₂, C₁-C₄ alkylamino,     alkylcarbonylamino, carbamoyl, C₁-C₄ alkylcarbamoyl, carbamoylamino,     C₁-C₄ alkylcarbamoylamino, alkylsulfonyl, sulfamoyl, alkylsulfamoyl,     alkylsulfonylamino, or two substituents form an alkylenedioxy group     or a haloalkylenedioxy group, still more preferably Ar¹ is a phenyl,     cyclohexyl, isobutyl or isopentyl group, said phenyl or cyclohexyl,     group being optionally substituted by one or more group(s) selected     from halo preferably bromo, chloro or fluoro, cyano, C₁-C₄ alkyl     preferably methyl, C₁-C₄ haloalkyl preferably CF₃ or CHF₂,     cycloalkyl, aryl preferably phenyl, heteroaryl preferably hydroxyl,     C₁-C₄ alkoxy preferably methoxy, C₁-C₄ haloalkoxy preferably OCF₃ or     OCHF₂, C₁-C₄ alkylamino, alkylcarbonylamino, alkylsulfonyl, or two     substituents form an alkylenedioxy group or a haloalkylenedioxy     group, even more preferably Ar¹ is a phenyl or isobutyl group, said     phenyl group being optionally substituted by one or more group(s)     selected from halo preferably bromo, chloro or fluoro, cyano or     C₁-C₄ alkyl preferably methyl, alkoxy preferably methoxy; and/or -   R¹ is H or methyl, preferably R¹ is H; and/or -   R² is H; and/or -   Ar² is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C₂-C₆     alkyl group, each of which being optionally substituted by one or     more group(s) selected from halo preferably chloro and fluoro,     cyano, nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl,     cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl,     aralkyl, heteroaryl, benzoxazol-2-yl, heteroarylalkyl, hydroxyl,     hydroxyalkyl, alkoxy, haloalkoxy preferably OCF₃ or OCHF2,     alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy,     heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy,     arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl,     arylcarbonyl, alkoxycarbonyl, cycloalkyloxycarbonyl,     heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy,     arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, oxo, or two     substituents form an alkylenedioxy group or a haloalkylenedioxy     group, or two substituents form a cycloalkyl or heterocycloalkyl     moiety together with the cycloalkyl or heterocycloalkyl group they     are attached to, or fused to the aryl, heteroaryl, cycloalkyl or     heterocycloalkyl group may be one or more cycloalkyl, aryl,     heterocyclyl or heteroaryl moiety, each of said substituents being     optionally substituted by one or more further substituents selected     from halo, cyano, nitro, alkyl, hydroxyalkyl, haloalkyl preferably     CF₃, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally     substituted by a chloro or methyl group, preferably phenyl,     4-chlorophenyl, heteroaryl, cycloalkylalkyl, heteroalkyl, hydroxyl,     alkoxy, haloalkoxy preferably 1,1,1-trifluoroethyloxy, alkoxyalkyl     preferably methoxymethyl, cycloalkyloxy, cycloalkylalkyloxy     preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally     substituted with one fluoro, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, amino, alkylamino,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy preferably     carbamoylmethyloxy, carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl     preferably (piperidin-1-yl)sulfonyl, (morpholin-4-yl)sulfonyl,     arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl,     alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino,     oxo, aralkyl, heteroarylalkyl, alkoxyalkoxy, alkoxyalkyl, and     haloalkoxyalkyl, more preferably Ar² is an aryl or heteroaryl     preferably pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C₂-C₆     alkyl group, each of said aryl, heteroaryl, cycloalkyl and     heterocyclyl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro and fluoro, cyano,     nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, heterocyclyl, aryl,     aralkyl, heteroaryl, benzoxazol-2-yl, heteroarylalkyl, hydroxyl,     alkoxy, haloalkoxy preferably OCF₃ or OCHF₂, alkoxyalkoxy, aryloxy,     alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy,     aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or two substituents     form an alkylenedioxy group or a haloalkylenedioxy group, or fused     to the cycloalkyl or heterocycloalkyl group may be one aryl moiety,     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, cyano, nitro, alkyl preferably methyl, ethyl, propyl,     isopropyl, tert-butyl, haloalkyl preferably CF₃, cyanomethyl, alkoxy     preferably methoxy, ethoxy, isopropoxy, cycloalkyl,     cycloalkylalkyloxy, alkoxyalkoxy, aryloxy, aralkyloxy optionally     substituted with one fluoro, amino, alkylcarbonylamino, carbamoyl,     hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more     preferably Ar² is an aryl preferably phenyl, heteroaryl preferably     pyridyl, heterocyclyl preferably piperidinyl, C₂-C₆ alkyl group     preferably isobutyl, each of said aryl, heteroaryl and heterocyclyl     groups being optionally substituted by one or more group(s) selected     from halo preferably chloro and fluoro, cyano, nitro, alkyl     preferably methyl, heterocyclyl preferably pyrrolidin-1-yl,     4-methylpiperidin-1-yl, aryl, heteroaryl preferably pyridinyl,     pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazol-2-yl, alkoxy     preferably methoxy, ethoxy and isopropyloxy, alkoxyalkyl,     cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy     and 3,3-diphenylpropan-1-oxy heteroarylalkyloxy preferably     pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably     phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl,     arylcarbonyl, or two substituents form an haloalkylenedioxy group     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, more preferably fluoro, cyano, alkyl preferably methyl,     cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably     2-methoxyethoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy,     aryloxy preferably phenoxy, aralkyloxy optionally substituted with     one fluoro, preferably benzyloxy, 4-fluorobenzyloxy, amino,     alkylcarbonylamino preferably acetyl amino, alkylsulfonyl preferably     m ethyl sulfonyl, alkyl sulfonyl amino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino.

In one embodiment, preferred compounds of Formula I are those of formula Ib:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar¹ is as defined above in respect to formula I, preferably Ar¹ is a     5- to 6-membered aryl or heteroaryl group, or a 3- to 6-membered     cycloalkyl group, or a linear or branched C₃-C₆ alkyl group, each of     which being optionally substituted by one or more group(s) selected     from halo preferably bromo, chloro or fluoro, cyano, C₁-C₄ alkyl,     C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkyl preferably CF₃ or CHF₂,     cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl,     heterocyclylalkyl, aryl preferably phenyl, aralkyl, heteroaryl,     heteroarylalkyl, hydroxyl, C₁-C₄ alkoxy C₁-C₄ haloalkoxy preferably     OCF₃ or OCHF₂, C₁-C₄ alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, C₁-C₄ alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, C₁-C₄     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or two substituents     form an alkylenedioxy group or a haloalkylenedioxy group, or two     substituents form a cycloalkyl or heterocycloalkyl moiety together     with the cycloalkyl group they are attached to, or fused to the aryl     or heteroaryl group may be one or more cycloalkyl, aryl,     heterocyclyl or heteroaryl moiety, each of said substituents being     optionally substituted by one or more further substituents selected     from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,     cycloalkylalkyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy,     cycloalkyloxy, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino or oxo, more preferably Ar¹ is a 5- to     6-membered aryl preferably phenyl, 5- to 6-membered heteroaryl group     preferably pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl,     isopropyl, isobutyl or isopentyl each of said phenyl, pyridin-2-yl,     pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally     substituted by one or more group(s) selected from halo preferably     bromo, chloro or fluoro, cyano, C₁-C₄ alkyl preferably methyl, C₁-C₄     alkoxy preferably methoxy, aryl preferably phenyl, still more     preferably Ar¹ is aryl preferably phenyl, cyclohexyl, isobutyl or     isopentyl, said phenyl group being optionally substituted by one or     more halo group preferably bromo, chloro or fluoro, cyano, methyl,     phenyl or methoxy, further more preferably Ar¹ is phenyl,     cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl,     3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,     4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2-cyanophenyl,     3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, 1,1′-biphenyl-2-yl, 4-cyanophenyl, even more     preferably Ar¹ is isobutyl, cyclohexyl, phenyl, 2-chlorophenyl,     2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl,     2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, still even more preferably Ar¹ is isobutyl,     2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl,     2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl; -   L¹ is as defined above in respect to formula I, preferably L¹ is a     single bond or a methylene optionally being substituted by one or     more substituents selected from fluoro or methyl, more preferably L¹     is a single bond drawn as a solid or dotted wedge, even more     preferably a single bond drawn as a solid wedge; -   R¹ is as defined above in respect to formula I, preferably R¹ is H     or methyl, more preferably R¹ is H; -   E is as defined above in respect to formula I, preferably E is N; -   D is as defined above in respect of formula I, preferably D is CO; -   L² is as defined above in respect to formula I, preferably L² is a     single bond, C₁-C₃ alkylene optionally being substituted by one or     more substituents selected from fluoro or methyl, more preferably L²     is a single bond; -   Ar² is as defined above in respect to formula I, preferably Ar² is     an aryl or heteroaryl, cycloalkyl, heterocyclyl or C₂-C₆ alkyl     group, each of which being optionally substituted by one or more     group(s) selected from halo preferably chloro and fluoro, cyano,     nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl,     cycloalkyl alkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl,     aryl, aralkyl, heteroaryl, benzoxazol-2-yl, heteroarylalkyl,     hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably OCF₃ or OCHF₂,     alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy,     heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy,     arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl,     arylcarbonyl, alkoxycarbonyl, cycloalkyloxycarbonyl,     heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy,     arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, oxo, or two     substituents form an alkylenedioxy group or a haloalkylenedioxy     group, or two substituents form a cycloalkyl or heterocycloalkyl     moiety together with the cycloalkyl or heterocyclyl group they are     attached to, or fused to the aryl, heteroaryl, cycloalkyl or     heterocyclyl group may be one or more cycloalkyl, aryl, heterocyclyl     or heteroaryl moiety, each of said substituents being optionally     substituted by one or more further substituents selected from halo,     cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl,     cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or     methyl group, preferably phenyl, 4-chlorophenyl, 4-tolyl,     heteroaryl, cycloalkylalkyl, heteroalkyl, aralkyl, heteroarylalkyl,     hydroxyl, alkoxy, alkoxyalkyl preferably methoxymethyl,     alkoxyalkoxy, haloalkoxy haloalkoxy preferably trifluoromethoxy,     1,1,1-trifluoroethyloxy, cycloalkyloxy, cycloalkylalkyloxy     preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally     substituted by one fluoro, alkoxyalkyl, haloalkoxyalkyl, amino,     alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,     cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy     preferably carbamoylmethyloxy, carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl     preferably (piperidin-1-yl)sulfonyl, (morpholin-4-yl)sulfonyl,     arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl,     alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino,     oxo, more preferably Ar² is an aryl or heteroaryl preferably     pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C₂-C₆ alkyl group,     each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl     groups being optionally substituted by one or more group(s) selected     from halo preferably chloro and fluoro, cyano, nitro, alkyl,     haloalkyl preferably CF₃ or CHF₂, heterocyclyl, aryl, aralkyl,     heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably     OCF₃ or OCHF₂, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy,     heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl,     heteroaryloxyalkyl, arylcarbonyl, or two substituents form an     alkylenedioxy group or a haloalkylenedioxy group, or fused to the     cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of     said substituents being optionally substituted by one or more     further substituents selected from halo preferably chloro or fluoro,     cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably CF₃, cyanomethyl, alkoxy preferably     methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by     one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino,     carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino,     still more preferably Ar² is an aryl preferably phenyl, heteroaryl     preferably pyridyl, heterocyclyl preferably piperidinyl, C₂-C₆ alkyl     group preferably isobutyl, each of said aryl, heteroaryl and     heterocyclyl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro and fluoro, cyano,     nitro, alkyl, preferably methyl, heterocyclyl preferably     pyrrolidin-1-yl, 4-methylpiperidin-1-yl, aryl preferably phenyl,     heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl,     pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy,     alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy,     phenethyloxy or 3,3-diphenylpropan-1-oxy, heteroarylalkyloxy     preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl     preferably phenoxymethyl, heteroaryloxyalkyl preferably     pyridinyloxymethyl, arylcarbonyl preferably phenylacetyl, or two     substituents form an haloalkylenedioxy group each of said     substituents being optionally substituted by one or more further     substituents selected from halo preferably chloro or fluoro, more     preferably fluoro, cyano, nitro, alkyl preferably methyl,     cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl     preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy,     aryloxy preferably phenoxy, aralkyloxy optionally substituted by one     fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino,     alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably     methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, further more preferably Ar² is a     biaryl consisting of two 6-membered aryl moieties preferably     biphenyl, more preferably a biphenyl linked to L² at position 4′ and     monosubstituted at position 2, or Ar² is a heterobiaryl consisting     of one 6-membered aryl moiety and one 6-membered heteroaryl moiety     or two 6-membered heteroaryl moieties, said heterobiaryl being     linked to L² either on the aryl or on the heteroaryl moiety and     being preferably phenylpyridyl, pyrimidinylphenyl,     pyridazinylphenyl, pyrazinylphenyl, or Ar² is an aryl or heteroaryl     optionally substituted by one group selected from arylalkyloxy,     aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl     and heteroaryl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, cyano,     nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy     optionally substituted by one fluoro preferably benzyloxy or     4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino,     alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, or Ar² is a piperidinyl ring     linked to L² at position 4 and N substituted with a phenyl,     4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said     phenyl moiety being further substituted by one or more substituents     selected from halo preferably chloro and fluoro, cyano, nitro, alkyl     preferably methyl, haloalkyl preferably CF₃, alkoxy preferably     methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl,     (morpholin-4-yl)sulfonyl, alksulfamoyl preferably     methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar²     is 4′-(2-methoxy-1,1′-biphenyl), 4′-(2-methyl-1,1′-biphenyl),     4′-(2-fluoro-1,1′-biphenyl), 4′-(4-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl), 4′-(2-chloro-2′-methoxy-1,1′-biphenyl),     4′-(2-(2-methoxyethoxy)-1,1′-biphenyl),     4′-(2-(methoxymethyl)-1,1′-biphenyl), 4′-(4-methoxy-1,1′-biphenyl),     4′-(4-cyano-1,1′-biphenyl), 4′-(3-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl),     4′-(4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-trifluoromethoxy-1,1′-biphenyl),     4′-(2-isopropoxy-1,1′-biphenyl),     4′-(2-cyclopropylmethyloxy-1,1′-biphenyl),     4′-(2-cyano-1,1′-biphenyl), 4′-(2,6-dimethoxy-1,1′-biphenyl),     4′-(2,4-dichloro-1,1′-biphenyl),     4′-(2-trifluoromethyl-1,1′-biphenyl),     4′-(2-methoxy-4-chloro-1,1′-biphenyl),     4′-(2,4-dimethoxy-1,1′-biphenyl), 4-(2,2′-dimethoxy-1,1′-biphenyl),     4-(naphtalen-2-yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl,     4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl,     4-(2-methoxypyridin-3-yl)phenyl,     4-(2,6-dimethoxy-pyridin-3-yl)phenyl,     4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl,     4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl,     4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl,     4-(2,4-dimethoxypyrimidin-6-yl)phenyl,     4-(2,4-dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl,     4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl,     (4-phenoxymethyl)phenyl, optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, more     preferably fluoro, alkyl preferably methyl, alkoxy preferably     methoxy, or Ar² is 4′-(2,4-difluoro-1,1′-biphenyl),     4′-(3′-methyl-1,1′-biphenyl), 4′-(3′-fluoro-1,1′-biphenyl),     4′-(2-fluoro-4-methoxy-1,1′-biphenyl),     4′-(4-fluoro-2-methoxy-1,1′-biphenyl),     4′-(2,3-dimethoxy-1,1′-biphenyl), 4′-(3,4-dimethoxy-1,1′-biphenyl),     4′-(2,3,4-trimethoxy-1,1′-biphenyl),     4′-(2,3,6-trimethoxy-1,1′-biphenyl),     4′-(3,5-dimethoxy-1,1′-biphenyl), 4′-(2,5-dimethoxy-1,1′-biphenyl),     4′-(2-isopropyl-1,1′-biphenyl), 4′-(2,2′-dimethoxy-1,1′-biphenyl),     4′-(2′-fluoro,2-dimethoxy-1,1′-biphenyl),     4′-(2-ethyl-1,1′-biphenyl), 4′-(4-propyl-1,1′-biphenyl),     4′-(4-tert-butyl-1,1′-biphenyl),     4′-(2-methoxy-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methoxy-4-acetylamino-1,1′-biphenyl),     4′-(3-hydroxycarbamimidoyl-1,1′-biphenyl),     4′-(4-amino-2-methoxy-1,1′-biphenyl),     4′-(3-carbamoyl-1,1′-biphenyl),     4′-(5-cyano-2,3-dimethoxy-1,1′-biphenyl),     4′-(2-cyano-4,5-dimethoxy-1,1′-biphenyl),     4′-(3,4,5-trimethoxy-1,1′-biphenyl), 4′-(2-cyano     methyl-4,5-dimethoxy-1,1′-biphenyl),     4′-(2-fluoro-5-cyano-1,1′-biphenyl),     4′-(2′-fluoro-3,4-dimethoxy-1,1′-biphenyl),     4′-(3-carbamoyl-4-cyano-1,1′-biphenyl),     4′-(2-cyano-4-methoxy-1,1′-biphenyl),     4′-(2′-fluoro-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2′-fluoro-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-cyano-2′-fluoro-1,1′-biphenyl),     4′-(2-chloro-5-cyano-1,1′-biphenyl),     4′-(2-cyano-4-trifluoromethyl-1,1′-biphenyl),     4′-(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(4-methylsulfonyl-1,1′-biphenyl),     4′-(3-methylsulfonylamino-1,1′-biphenyl),     4′-(4-amino-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methoxy-1,1′-biphenyl), 4′-(3-cyano-1,1′-biphenyl),     4′-(2-cyano-3-methoxy-1,1′-biphenyl),     4′-(2-methyl-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methyl-3-acetylamino-1,1′-biphenyl),     4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl,     4-(2-ethoxypyridin-5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl,     4-(2-methoxy-6-methylpyridin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl,     4-(2,6-dimethylpyridin-5-yl)phenyl,(2,6dimethoxy-pyrimidin-5-yl)-3-chlorophenyl,     4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl,     4-(4,6-dimethoxy-pyridin-3-yl)phenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)phenyl,     4-(2,6-dimethoxy-pyridin-3-yl)phenyl,     4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl,     dimethoxy-pyridin-3-yl)-3-fluorophenyl,     4-(6-methoxy-pyridin-3-yl)-3-fluorophenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl,     4-(4,6-dimethoxy-pyrimidin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-5-yl)-3-methoxyphenyl,     4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3-yl)phenyl,     4-(2-methoxy-pyrimidin-3-yl)phenyl,     3-methoxy-2-(2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(5-cyano-2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl,     2-(2,4-dimethoxyphenyl)pyridin-5-yl,     1-(2-cyano-4-trifluoromethyl)piperidin-4-yl,     1-(2-nitro-4-trifluoromethyl)piperidin-4-yl,     1-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; -   R² is H; -   L³ is as defined above in respect to formula I, preferably L³ is a     single bond, C₁-C₃ alkylene optionally substituted by one or more     group(s) selected from chloro, fluoro, alkyl preferably methyl,     alkoxy preferably methoxy, or haloalkyl, preferably L³ is a single     bond, more preferably L³ is a single bond drawn as a solid wedge; -   Z is as defined above in respect to formula I, preferably Z is COOR     where R is as defined above in respect of formula I, more preferably     Z is COOH; -   R³ is as defined above in respect to formula I, preferably R³ is H,     cyano, alkyl, preferably methyl, aralkyl, preferably benzyl,     hydroxyalkyl preferably hydroxymethyl, alkoxyalkyl preferably     methoxymethyl, acetyl linked to the E containing ring by a bond     drawn as a dotted wedge, arylsulfonyl preferably phenylsulfonyl,     more preferably R³ is H; -   R^(3′) is as defined above in respect of formula I, preferably     R^(3′) is H or methyl, more preferably R^(3′) is H; -   R⁴ is as defined above in respect to formula I, preferably R⁴ is H,     cyano or methyl, more preferably R⁴ is H; -   R^(4′) is as defined above in respect to formula I, preferably     R^(4′) is H or methyl, more preferably R^(4′) is H; -   the bond represented by the dotted line is either absent or present,     preferably the dotted line is absent.

Particularly preferred compounds of formula Ib are those of formula Ib-1a

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar¹, Ar², R¹, R², R³, R^(3′), R⁴, R^(4′), L², L³, D and Z are as defined above in respect of formula Ib. Preferred compounds of formula Ib-1a are those of formula Ib-1b

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar¹, Ar², R¹, R², R³, R^(3′), R⁴, R^(4′), L² and D are as defined above in respect of formula Ib and R is as defined above in respect of formula I.

Preferred compounds of formula Ib-1b are those of formula Ib-1c

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar¹, Ar², R¹, R², L² and D are as defined above in respect of formula Ib and R is as defined above in respect of formula I.

Other preferred compounds of formula Ib-1b are those of formula Ib-1b′

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R² is as defined above in respect of formula Ib and R is as defined     above in respect of formula I; -   R¹ is H; -   D is C═O; -   L² is single bond; -   Ar¹ is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-membered     cycloalkyl group, or a linear or branched C₃-C₆ alkyl group, each of     which being optionally substituted by one or more group(s) selected     from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl,     hydroxyl, alkoxy, haloalkoxy, amino, alkylamino, carboxy,     alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,     haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino, or two substituents form an alkylenedioxy     group or a haloalkylenedioxy group, each of said aryl or heteroaryl     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl,     alkoxy, haloalkoxy, preferably Ar¹ is a 5- to 6-membered aryl     preferably phenyl, 5- to 6-membered heteroaryl group preferably     pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl,     isobutyl or isopentyl each of said phenyl, pyridin-2-yl,     pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally     substituted by one or more group(s) selected from halo preferably     bromo, chloro or fluoro, cyano, C₁-C₄ alkyl preferably methyl, C₁-C₄     alkoxy preferably methoxy, aryl preferably phenyl, still more     preferably Ar¹ is aryl preferably phenyl, cyclohexyl, isobutyl or     isopentyl, said phenyl group being optionally substituted by one or     more halo group preferably bromo, chloro or fluoro, cyano, methyl,     phenyl or methoxy, further more preferably Ar¹ is phenyl,     cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl,     3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,     4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2-cyanophenyl,     3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, 1,1′-biphenyl-2-yl, 4-cyanophenyl, even more     preferably Ar¹ is isobutyl, cyclohexyl, phenyl, 2-chlorophenyl,     2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl,     2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, still even more preferably Ar¹ is isobutyl,     2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl,     2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl; -   Ar² is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C₂-C₆     alkyl group, each of which being optionally substituted by one or     more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl,     cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl,     heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl     heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy,     alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,     aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, amino,     alkylamino, arylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl,     heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy,     heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl,     alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl,     alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, oxo,     or two substituents form an alkylenedioxy group or a     haloalkylenedioxy group, or fused to the aryl, heteroaryl,     cycloalkyl or heterocyclyl group may be one or more aryl or     heteroaryl moiety, each of said substituents being optionally     substituted by one or more further substituents selected from halo,     cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl,     cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or     methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy,     alkoxyalkyl, alkoxyalkoxy, haloalkoxy, cycloalkyloxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by a     fluoro or alkyl or cycloalkyl group, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, amino, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl,     arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino, oxo, alkoxyalkoxy, alkoxyalkyl, and     haloalkoxyalkyl; preferably Ar² is an aryl or heteroaryl preferably     pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C₂-C₆ alkyl group,     each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl     groups being optionally substituted by one or more group(s) selected     from halo preferably chloro and fluoro, cyano, nitro, alkyl,     haloalkyl preferably CF₃ or CHF₂, heterocyclyl, aryl, aralkyl,     heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably     OCF₃ or OCHF₂, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy,     heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl,     heteroaryloxyalkyl, arylcarbonyl, or two substituents form an     alkylenedioxy group or a haloalkylenedioxy group, or fused to the     cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of     said substituents being optionally substituted by one or more     further substituents selected from halo preferably chloro or fluoro,     cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably CF₃, cyanomethyl, alkoxy preferably     methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by     one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino,     carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino,     still more preferably Ar² is an aryl preferably phenyl, heteroaryl     preferably pyridyl, heterocyclyl preferably piperidinyl, C₂-C₆ alkyl     group preferably isobutyl, each of said aryl, heteroaryl and     heterocyclyl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro and fluoro, cyano,     nitro, alkyl, preferably methyl, heterocyclyl preferably     pyrrolidin-1-yl, 4-methylpiperidin-1-yl, aryl preferably phenyl,     heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl,     pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy,     alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy,     phenethyloxy or 3,3-diphenylpropan-1-oxy, heteroarylalkyloxy     preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl     preferably phenoxymethyl, heteroaryloxyalkyl preferably     pyridinyloxymethyl, arylcarbonyl preferably phenylacetyl, or two     substituents form an haloalkylenedioxy group each of said     substituents being optionally substituted by one or more further     substituents selected from halo preferably chloro or fluoro, more     preferably fluoro, cyano, nitro, alkyl preferably methyl,     cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl     preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy,     aryloxy preferably phenoxy, aralkyloxy optionally substituted by one     fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino,     alkylcarbonylamino preferably acetylamino, alkyl sulfonyl preferably     methyl sulfonyl alkyl sulfonyl amino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, further more preferably Ar² is a     biaryl consisting of two 6-membered aryl moieties preferably     biphenyl, more preferably a biphenyl linked to L² at position 4′ and     monosubstituted at position 2, or Ar² is a heterobiaryl consisting     of one 6-membered aryl moiety and one 6-membered heteroaryl moiety     or two 6-membered heteroaryl moieties, said heterobiaryl being     linked to L² either on the aryl or on the heteroaryl moiety and     being preferably phenylpyridyl, pyrimidinylphenyl,     pyridazinylphenyl, pyrazinylphenyl, or Ar² is an aryl or heteroaryl     optionally substituted by one group selected from arylalkyloxy,     aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl     and heteroaryl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, cyano,     nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy     optionally substituted by one fluoro preferably benzyloxy or     4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino,     alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, or Ar² is a piperidinyl ring     linked to L² at position 4 and N substituted with a phenyl,     4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said     phenyl moiety being further substituted by one or more substituents     selected from halo preferably chloro and fluoro, cyano, nitro, alkyl     preferably methyl, haloalkyl preferably CF₃, alkoxy preferably     methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl,     (morpholin-4-yl)sulfonyl, alksulfamoyl preferably     methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar²     is 4′-(2-methoxy-1,1′-biphenyl), 4′-(2-methyl-1,1′-biphenyl),     4′-(2-fluoro-1,1′-biphenyl), 4′-(4-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl), 4′-(2-chloro-2′-methoxy-1,1′-biphenyl),     4′-(2-(2-methoxyethoxy)-1,1′-biphenyl),     4′-(2-(methoxymethyl)-1,1′-biphenyl), 4′-(4-methoxy-1,1′-biphenyl),     4′-(4-cyano-1,1′-biphenyl), 4′-(3-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl),     4′-(4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-trifluoromethoxy-1,1′-biphenyl),     4′-(2-isopropoxy-1,1′-biphenyl),     4′-(2-cyclopropylmethyloxy-1,1′-biphenyl),     4′-(2-cyano-1,1′-biphenyl), 4′-(2,6-dimethoxy-1,1′-biphenyl),     4′-(2,4-dichloro-1,1′-biphenyl),     4′-(2-trifluoromethyl-1,1′-biphenyl),     4′-(2-methoxy-4-chloro-1,1′-biphenyl),     4′-(2,4-dimethoxy-1,1′-biphenyl), 4-(2,2′-dimethoxy-1,1′-biphenyl),     4-(naphtalen-2-yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl,     4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl,     4-(2-methoxypyridin-3-yl)phenyl, dimethoxy-pyridin-3-yl)phenyl,     4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl,     4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl,     4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl,     4-(2,4-dimethoxypyrimidin-6-yl)phenyl,     4-(2,4-dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl,     4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl,     (4-phenoxymethyl)phenyl, optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, more     preferably fluoro, alkyl preferably methyl, alkoxy preferably     methoxy, or Ar² is 4′-(2,4-difluoro-1,1′-biphenyl),     4′-(3′-methyl-1,1′-biphenyl), 4′-(3′-fluoro-1,1′-biphenyl),     4′-(2-fluoro-4-methoxy-1,1′-biphenyl),     4′-(4-fluoro-2-methoxy-1,1′-biphenyl),     4′-(2,3-dimethoxy-1,1′-biphenyl), 4′-(3,4-dimethoxy-1,1′-biphenyl),     4′-(2,3,4-trimethoxy-1,1′-biphenyl),     4′-(2,3,6-trimethoxy-1,1′-biphenyl),     4′-(3,5-dimethoxy-1,1′-biphenyl), 4′-(2,5-dimethoxy-1,1′-biphenyl),     4′-(2-isopropyl-1,1′-biphenyl), 4′-(2,2′-dimethoxy-1,1′-biphenyl),     4′-(2′-fluoro,2-dimethoxy1,1′-biphenyl), 4′-(2-ethyl-1,1′-biphenyl),     4′-(4-propyl-1,1′-biphenyl), 4′-(4-tert-butyl-1,1′-biphenyl),     4′-(2-methoxy-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methoxy-4-acetylamino-1,1′-biphenyl),     4′-(3-hydroxycarbamimidoyl-1,1′-biphenyl),     4′-(4-amino-2-methoxy-1,1′-biphenyl),     4′-(3-carbamoyl-1,1′-biphenyl),     4′-(5-cyano-2,3-dimethoxy-1,1′-biphenyl),     4′-(2-cyano-4,5-dimethoxy-1,1′-biphenyl),     4′-(3,4,5-trimethoxy-1,1′-biphenyl), 4′-(2-cyano     methyl-4,5-dimethoxy-1,1′-biphenyl),     4′-(2-fluoro-5-cyano-1,1′-biphenyl),     4′-(2′-fluoro-3,4-dimethoxy1,1′-biphenyl),     4′-(3-carbamoyl-4-cyano-1,1′-biphenyl),     4′-(2-cyano-4-methoxy-1,1′-biphenyl),     4′-(2′-fluoro-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2′-fluoro-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-cyano-2′-fluoro-1,1′-biphenyl),     4′-(2-chloro-5-cyano-1,1′-biphenyl),     4′-(2-cyano-4-trifluoromethyl-1,1′-biphenyl),     4′-(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(4-methylsulfonyl-1,1′-biphenyl),     4′-(3-methylsulfonylamino-1,1′-biphenyl),     4′-(4-amino-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methoxy-1,1′-biphenyl), 4′-(3-cyano-1,1′-biphenyl),     4′-(2-cyano-3-methoxy-1,1′-biphenyl),     4′-(2-methyl-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methyl-3-acetylamino-1,1′-biphenyl),     4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl,     4-(2-ethoxypyridin-5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl,     4-(2-methoxy-6-methylpyridin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl,     4-(2,6-dimethylpyridin-5-yl)phenyl,     4-(2,6-dimethoxy-pyrimidin-5-yl)-3-chlorophenyl,     4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl,     4-(4,6-dimethoxy-pyridin-3-yl)phenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)phenyl,     4-(2,6-dimethoxy-pyridin-3-yl)phenyl,     4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(2,6-dimethoxy-pyridin-3-yl)-3-fluorophenyl,     4-(6-methoxy-pyridin-3-yl)-3-fluorophenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl,     4-(4,6-dimethoxy-pyrimidin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-5-yl)-3-methoxyphenyl,     4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3-yl)phenyl,     4-(2-methoxy-pyrimidin-3-yl)phenyl,     3-methoxy-2-(2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(5-cyano-2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl,     2-(2,4-dimethoxyphenyl)pyridin-5-yl,     1-(2-cyano-4-trifluoromethyl)piperidin-4-yl,     1-(2-nitro-4-trifluoromethyl)piperidin-4-yl,     1-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; -   R³ is H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl,     arylsulfonyl; -   R^(3′) is H or C₁-C₄ alkyl; -   R⁴ is H, cyano, C₁-C₄ alkyl.

Preferred compounds of formula Ib-1c or Ib-1b′ are those of formula Ib-1d

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar¹, Ar², R¹ and R² are as defined above in respect of formula Ib in case of preferred compounds of formula Ib-1c, or Ib-1b′ in case of preferred compounds of formula Ib-1b′, and R is as defined above in respect of formula I.

Preferred compounds of formula Ib-1d are those of formula Ib-1e

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein Ar², R¹ and R² are as defined above in respect of formula Ib or Ib-1b′;

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are independently selected from H,     halo preferably fluoro, chloro, bromo, cyano, alkyl, hydroxyalkyl,     haloalkyl preferably CF₃ or CHF₂, cycloalkyl, cycloalkylalkyl,     heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably     phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, haloalkoxy     preferably OCF₃ or OCHF₂, heterocyclyloxy, alkylamino,     alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl,     aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy,     cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy,     heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of     R⁸ and R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′) and R^(8′)     form an alkylenedioxy group or a haloalkylenedioxy group together     with the phenyl group they are attached to, or one or more of R⁸ and     R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′) and R^(8′) form     together a cycloalkyl, aryl, heterocycloalyl or heteroaryl moiety     fused to the phenyl group they are attached to, each of said     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, hydroxyalkyl,     haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl,     alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy,     alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino or oxo, preferably R⁸, R^(8′), R⁹, R^(9′) and     R¹⁰ are independently selected from H, halo preferably fluoro,     chloro, bromo, cyano, alkyl, haloalkyl preferably CF₃ or CHF₂,     cycloalkyl, aryl preferably phenyl, heteroaryl, hydroxyl, haloalkoxy     preferably OCF₃ or OCHF₂, alkylamino, alkoxycarbonyl,     alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or one     or more of R⁸ and R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′)     and R^(8′) form an alkylenedioxy group or a haloalkylenedioxy group     together with the phenyl group they are attached to, each of said     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl,     alkoxy, haloalkoxy, more preferably R⁸, R^(8′), R⁹, R^(9′) and R¹⁰     are independently selected from H, halo preferably bromo, fluoro or     chloro, cyano, C₁-C₄ alkyl preferably methyl, aryl preferably     phenyl, alkoxy preferably methoxy, still more preferably R⁸, R^(8′),     R⁹, R^(9′) and R¹⁰ are independently selected from H, halo     preferably bromo, fluoro or chloro, alkyl preferably methyl, still     more preferably R⁸ is Br, Cl or F, preferably Cl and R^(8′), R⁹,     R^(9′) and R¹⁰ are independently selected from H or F, or R⁹ is Cl     or F and R⁸, R^(8′), R^(9′) and R¹⁰ are H, or R⁹ and R^(9′) are F     and R⁸, R^(8′) and R¹⁰ are H, or R¹⁰ is Cl or F and R⁸, R^(8′), R⁹     and R^(9′) are H, even more preferably R⁸ is Br, Cl or F and R^(8′),     R⁹, R^(9′) and R¹⁰ are H, or R⁸ and R⁹ are F and R^(8′), R^(9′) and     R¹⁰ are H, or R⁸ and R¹⁰ are F and R^(8′), R⁹ and R^(9′) are H.

Preferred compounds of formula Ib-1e are those of formula Ib-1f

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar² is as defined above in respect of formula Ib or Ib-1b′; -   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect of     formula Ib-1e.

Preferred compounds of formula Ib-1f are those of formula Ib-1g

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect of     formula Ib-1e; -   R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from     H, halo preferably chloro and fluoro more preferably chloro, cyano,     nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl,     cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl,     aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl,     alkoxy, haloalkoxy preferably —OCF₃ or —OCHF₂, alkoxyalkoxy,     cycloalkyloxy, heterocyclyloxy, aryloxy, hetero aryloxy,     alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl,     alkyloxycarbonyl, aminoalkylalkoxycarbonyl, cycloalkyloxycarbonyl,     heterocyclyloxy carbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy,     arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of     R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and     R^(11′) form an alkylenedioxy group or a haloalkylenedioxy group     together with the phenyl group they are attached to, or one or more     of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and     R^(11′) form together a cycloalkyl, aryl, heterocycloalkyl or     heteroaryl moiety fused to the phenyl group they are attached to,     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,     cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted     by one a chloro or methyl group, heteroaryl, cycloalkylalkyl,     aralkyl, heteroarylalkyl, heteroalkyl, hydroxyl, alkoxy,     alkoxyalkoxy, haloalkoxy preferably trifluoromethoxy,     1,1,1-trifluoroethyloxy, alkoxyalkyl, haloalkoxyalkyl,     cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy,     aryloxy, aralkyloxy optionally substituted by one fluoro, amino,     alkylamino, carboxy, alkoxycarbonyl, alkylcarbonlyoxy,     cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy     preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably     phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, haloalkylsulfonylamino and oxo, preferably     R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from     H, halo preferably chloro and fluoro more preferably chloro, cyano,     nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl,     cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl,     aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl,     alkoxy, haloalkoxy preferably —OCF₃ or —OCHF₂, alkoxyalkoxy,     cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl,     haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl,     alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy,     alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, or one or more of R¹¹ and R¹², or R¹² and     R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form an     alkylenedioxy group or a haloalkylenedioxy group together with the     phenyl group they are attached to, or one or more of R¹¹ and R¹², or     R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form     together an aryl or heteroaryl moiety fused to the phenyl group they     are attached to, each of said substituents being optionally     substituted by one or more further substituents selected from halo     preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl,     alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl     optionally substituted by one a chloro or methyl group, heteroaryl,     heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably     1,1,1-trifluoroethyloxy, alkoxyalkyl, cycloalkyloxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy,     aralkyloxy optionally substituted by one fluoro, amino, alkylamino,     carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy,     alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy preferably     carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably     phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino and oxo, more preferably R¹¹, R^(11′), R¹²,     R^(12′) and R¹⁶ are independently selected from H, halo preferably     chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF₃ or     CHF₂, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,     hydroxyl, alkoxy, haloalkoxy preferably OCF₃ or OCHF₂, alkoxyalkoxy,     aryloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy,     alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or one     or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or     R^(12′) and R^(11′) form an alkylenedioxy group or a     haloalkylenedioxy group together with the phenyl group they are     attached to, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶     and R^(12′), or R^(12′) and R^(11′) form together an aryl, or     heteroaryl moiety fused to the phenyl group they are attached to,     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, cyanomethyl, cycloalkyl, heterocyclyl, alkoxy preferably     methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by     one fluoro, amino, alkylamino, alkylcarbonylamino, carbamoyl,     hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more     preferably R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently     selected from H, halo preferably chloro and fluoro, cyano, nitro,     alkyl preferably methyl, ethyl, isopropyl or isobutyl, haloalkyl     preferably CF₃ or CHF₂, cycloalkyl preferably cyclohexyl,     heterocyclyl preferably pyrrolidin-1-yl, 4-methylpiperidin-1-yl,     aryl preferably phenyl, heteroaryl preferably thiophenyl, pyridinyl,     pyrimidinyl, pyrazinyl, pyridazinyl, aralkyl preferably benzyl,     alkoxy preferably methoxy, ethoxy or isopropyloxy,     cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy     or 3,3-diphenylpropan-1-oxy, heteroarylalkyloxy preferably     pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably     phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, or     two substituents form an haloalkylenedioxy group each of said     substituents being optionally substituted by one or more further     substituents selected from halo preferably chloro or fluoro, cyano,     alkyl preferably methyl, haloalkyl preferably trifluoromethyl,     alkoxy preferably methoxy, isopropyloxy, isobutyloxy, alkoxyalkyl     preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy     preferably phenoxy, aralkyloxy optionally substituted by one fluoro,     preferably benzyloxy, 4-fluorobenzyloxy, amino, alkylcarbonylamino     preferably acetylamino, alkylsulfonyl preferably methylsulfonyl,     alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino.

Preferred compounds of formula Ib-1g are those of formula Ib-1g1

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect of     formula Ib-1e; -   R¹⁶ is as defined above in respect to formula Ib-1g, preferably R¹⁶     is selected from halo preferably chloro, alkyl preferably methyl or     isobutyl, cycloalkyl preferably cyclohexyl, aryl preferably phenyl,     heteroaryl preferably pyridyl, thiophen-3-yl, pyrimidinyl,     pyrazinyl, pyridazinyl, aralkyl preferably benzyl, alkoxy preferably     methoxy, isopropyloxy more preferably isopropyloxy, haloalkoxy,     preferably OCF₃, OCHF₂, more preferably OCF₃, cycloalkylalkyloxy     preferably cyclopropylmethyloxy, arylalkyloxy preferably     phenethyloxy or benzyloxy, heteroarylalkyloxy preferably     pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl,     heteroaryloxyalkyl preferably pyridyloxymethyl, arylcarbonyl     preferably phenylcarbonyl, each of said substituents being     optionally substituted by one or more further substituents selected     from halo preferably chloro or fluoro, more preferably fluoro,     cyano, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, trifluoromethyl, cyanomethyl, cycloalkyl, aryl     optionally substituted by a chloro or methyl group, hydroxyl, alkoxy     preferably methoxy, ethoxy, isopropoxy, haloalkoxy preferably     trifluoromethoxy, 1,1,1-trifluoroethyloxy, aryloxy preferably     phenoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy,     aralkyloxy optionally substituted by one fluoro preferably     benzyloxy, 4-fluorobenzyloxy, alkoxyalkyl preferably methoxymethyl,     alkoxyalkoxy preferably 2-methoxyethoxy, amino, alkylcarbonylamino     preferably acetylamino, carbamoyl, carbamoylmethyloxy,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonylamino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, oxo, more     preferably R¹⁶ is selected from alkyl preferably isobutyl, or R¹⁶ is     alkoxy preferably isopropyloxy, or R¹⁶ is heterocyclyl preferably     pyrrolidin-1-yl, 4-methylpiperidin-1-yl, or R¹⁶ is aryl preferably a     phenyl, preferably a phenyl monosubstituted at position 2 by one     group selected from halo preferably chloro or fluoro, more     preferably fluoro, cyano, alkyl preferably methyl, alkoxy preferably     methoxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy     preferably 2-methoxyethoxy, or R¹⁶ is 2,4-difluorophenyl,     2-fluoro-4-methoxyphenyl, 4-fluoro-2-methoxyphenyl,     2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl,     2,5-dimethoxyphenyl, 2-methoxy-4-methylsulfonylaminophenyl,     4-acetylamino-2-methoxyphenyl, 4-amino-2-methoxyhenyl,     5-cyano-2,3-dimethoxyphenyl, 2-cyano-4,5-dimethoxyphenyl,     3,4,5-trimethoxyphenyl, 2-cyano-4-methoxyphenyl,     3-methylsulfonylaminophenyl, 4-methylsulfonylaminophenyl,     2-chloro-5-cyanophenyl, 2-cyano-4-trifluoromethylphenyl,     2-methyl-3-(N-methyl-N-methylsulfonyl)aminophenyl,     2-methoxy-4-(N-methyl-N-methylsulfonyl)aminophenyl,     4-methylsulfonylphenyl, 3-methylsulfonylaminophenyl,     4-methylsulfonylaminophenyl, 3-amino-2-methyl,     5-cyano-2-methylphenyl, 5-cyano-2-methoxyphenyl,     2-methyl-3-methylsulfonylamino, 3-cyano-2-methoxyphenyl, or 11¹⁶ is     aralkyl preferably benzyl, or R¹⁶ is heteroaryl preferably     4,6-dimethoxypyrimidin-2-yl, 2-methoxypyrimidin-3-yl,     2,4-dimethoxypyrimidin-5-yl, 2-methoxypyridin-3-yl,     2,6-dimethoxy-pyridin-3-yl, 2-(2-methoxyethoxy)-pyridin-3-yl,     2-methoxypyrimidin-5-yl, 2,4-dimethoxypyrimidin-6-yl, preferably     2-methoxypyrimidin-3-yl, (2,4-dimethoxy)pyrimidin-5-yl,     2-methoxypyrimidin-5-yl, 2,6-dimethoxy-pyridin-3-yl, more preferably     (2,4-dimethoxy)pyrimidin-5-yl, 2,6-dimethoxy-pyridin-3-yl,     2-chloro-6-methoxypyrimidin-5-yl, 2-methoxy-6-methylpyridin-5-yl,     2,6-dimethylpyridin-5-yl, 2,6-dimethoxypyrimidin-5-yl,     4-methoxypyridin-3-yl, 2-methoxypyridin-5-yl,     2,4-dimethoxypyridin-5-yl, 2,6-dimethoxypyridazin-5-yl,     2,6-dimethoxypyridin-5-yl, 5-methoxypyridin-3-yl,     4,6-dimethoxypyrimidin-5-yl, 3-methoxypyridin-4-yl,     4-methoxypyridin-3-yl, or R¹⁶ is, arylalkyloxy preferably     phenethyloxy, benzyloxy, 2-fluorobenzyloxy, more preferably     2-fluorobenzyloxy, or R¹⁶ is aryloxyalkyl preferably phenoxymethyl.

Preferred compounds of formula Ib-1g1 are those of formula Ib-1g1a

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect of     formula Ib-1e; -   R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected from H,     halo preferably chloro and fluoro more preferably fluoro, cyano,     alkyl preferably methyl, haloalkyl preferably CF₃ or CHF₂,     cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, aryl,     aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy     preferably methoxy, ethoxy, isopropyloxy, haloalkoxy preferably OCF₃     or OCHF₂, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl,     cycloalkylalkyloxy, aryloxy, aralkyloxy, haloalkoxyalkyl,     alkylamino, alkylsulfonyl preferably methylsulfonyl,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylamino alkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino, preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are     independently selected from H, halo preferably chloro and fluoro     more preferably fluoro, cyano, alkyl preferably methyl, haloalkyl     preferably CF₃ or CHF₂, cycloalkyl, heteroalkyl, heterocyclyl, aryl,     heteroaryl, hydroxyl, alkoxy preferably methoxy, ethoxy,     isopropyloxy, haloalkoxy preferably OCF₃ or OCHF₂, alkoxyalkoxy,     cycloalkyloxy, alkoxyalkyl, cycloalkylalkyloxy, aryloxy, aralkyloxy,     alkylamino, alkylsulfonyl preferably methylsulfonyl,     alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, haloalkylsulfonyl, cycloalkylsulfonyl,     sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, haloalkylsulfonylamino, more preferably     R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected from H,     halo preferably chloro and fluoro more preferably chloro, cyano,     alkyl preferably methyl, haloalkyl preferably CF₃ or CHF7, alkoxy     preferably methoxy, haloalkoxy preferably OCF₃ or OCHF₂,     alkoxyalkoxy preferably (2-methoxy)ethoxy, alkylamino preferably     dimethylamino, more preferably R^(17′), R^(18′) and R¹⁹ are H and     R¹⁷ is methoxy, (2-methoxy)ethoxy or R¹⁷, R^(18′) and R¹⁹ are H and     R^(17′) is methoxy, or R¹⁷, R^(17′) and R^(18′) are H and R¹⁹ is     chloro, methyl, methoxy, dimethylamino, or R^(17′) and R^(18′) are H     and: a) both R¹⁷ and R¹⁹ are methyl or methoxy, or b) R¹⁷ is methyl     and R¹⁹ is methoxy, or R¹⁷, R^(17′) and R¹⁹ are H and R^(18′) is     methoxy even more preferably R^(17′), R^(18′) and R¹⁹ are H and R¹⁷     is methoxy, or R^(17′) and R^(18′) are H and: a) both R¹⁷ and R¹⁹     are methyl or methoxy, or b) R¹⁷ is methyl and R¹⁹ is methoxy, or     R¹⁷, R^(17′) and R¹⁹ are H and R^(18′) is methoxy.

Other preferred compounds of formula Ib-1g are those of formula Ib-1g2

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Ib-1e; -   R¹² and R^(12′) are as defined above in respect to formula Ib-1g,     preferably R¹² and R^(12′) are independently selected from H, halo     preferably chloro, cyano, nitro, alkyl preferably ethyl, isopropyl,     haloalkyl preferably CF₃ or CHF₂, aryl preferably phenyl, hydroxyl,     alkoxy preferably methoxy or ethoxy, haloalkoxy preferably OCF₃ or     OCHF2, alkoxyalkoxy, aryloxy, arylalkyloxy preferably phenethyloxy     or benzyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl,     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, alkoxy, alkyl, cycloalkyl, alkylsulfonyl preferably     methylsulfonyl, more preferably R¹² is H or alkoxy preferably     methoxy or ethoxy, more preferably methoxy and R^(12′) is halo     preferably chloro, alkoxy preferably methoxy or ethoxy, more     preferably methoxy, arylalkyloxy preferably phenethyloxy, benzyloxy     or 3,3-diphenylpropan-1-oxy, optionally substituted by halo     preferably chloro or fluoro, alkoxy, alkyl, alkylsulfonyl preferably     methylsulfonyl, even more preferably R¹² is methoxy and R^(12′) is     methoxy, chloro, benzyloxy, (4-chlorobenzyl)oxy,     (4-methylsulfonylbenzyl)oxy.

Other preferred compounds of formula Ib-1g are those of formula Ib-1h

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Ib-1e; -   L⁴ is a single bond, —C(O), —O—, —O—C₁-C₃-alkylene or     —C₁-C₃-alkylene-O— optionally substituted by one or more group     selected from fluoro or methyl, preferably L⁴ is a single bond, —O—,     —O—C₁-C₂-alkylene, —C₁-alkylene-O— optionally substituted by one or     more group selected from fluoro or methyl, more preferably L⁴ is a     single bond, —OCH₂, —O(CH₂)₂— or —CH₂O—; -   R¹¹, R^(11′), R¹² and R^(12′) are as defined above in respect to     formula Ib-1g, preferably R¹¹ and R^(11′) are H and R¹² and R^(12′)     are independently selected from H, halo preferably chloro or fluoro,     cyano, nitro, alkyl preferably methyl, ethyl, isopropyl, haloalkyl     preferably CF₃ or CHF₂, hydroxyl, alkoxy preferably methoxy or     ethoxy, haloalkoxy preferably OCF₃ or OCHF₂, alkoxyalkoxy, more     preferably R¹¹ and R^(11′) are H, R¹² is H, fluoro, chloro, methyl,     —CF₃, alkoxy preferably methoxy or ethoxy, more preferably methoxy     and R^(12′) is halo preferably chloro, alkoxy preferably methoxy or     ethoxy, more preferably methoxy, or R¹¹, R^(11′) and R^(12′) are H     and R¹² is fluoro, chloro, methyl, CF₃, methoxy, even more     preferably R¹¹ and R^(11′) are H, R¹² is H or methoxy and R^(12′) is     methoxy, chloro, or R¹¹, R^(11′) and R^(12′) are H and R¹² is     fluoro, chloro, methyl, CF₃, methoxy; -   R¹³, R^(13′), R¹⁴, R^(14′) and R¹⁵ are independently selected from     H, halo preferably chloro and fluoro more preferably fluoro, cyano,     alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl,     haloalkyl preferably CF₃ or CHF₂, cyanomethyl, cycloalkyl,     heteroalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, hydroxyalkyl,     alkoxy preferably methoxy, haloalkoxy preferably OCF₃, OCHF₂, or     1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl,     cycloalkylalkyloxy, aralkyloxy optionally substituted by one fluoro,     haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy,     alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl,     alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, haloalkylsulfonylamino, preferably R¹³,     R^(13′), R¹⁴, R^(14′) and R¹⁵ are independently selected from H,     halo preferably chloro and fluoro more preferably fluoro, cyano,     alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl,     haloalkyl preferably CF₃ or CHF₂, cycloalkyl, cycloalkylalkyl,     heteroalkyl, heterocyclyl, aryl, aralkyl, heteroaryl,     heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy,     haloalkoxy preferably OCF₃, OCHF₂, or 1,1,1-trifluoroethyloxy,     alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl, cycloalkylalkyloxy,     aralkyloxy optionally substituted by one fluoro, haloalkoxyalkyl,     amino, alkylamino, alkylcarbonylamino, haloalkylcarbonylamino,     carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy,     carbamoylamino, alkylcarbamoylamino, carbamimidoyl,     hydroxycarbamimidoyl, alkylsulfonyl preferably methylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl, alkylsulfamoyl,     alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino,     more preferably R¹³, R^(13′), R¹⁴, R^(14′) and R¹⁵ are independently     selected from H, halo preferably chloro and fluoro more preferably     fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably —CF₃ or CHF₂, hydroxyl,     hydroxyalkyl, alkoxy preferably methoxy, haloalkoxy preferably OCF₃     or OCHF₂, alkoxyalkoxy preferably 2-methoxyethoxy, cycloalkyloxy,     cycloalkylalkyloxy, alkoxyalkyl preferably methoxymethyl,     haloalkoxyalkyl, amino, alkylcarbonylamino preferably acetylamino,     carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl preferably     methylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl,     alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, still more preferably R¹³,     R^(13′), R¹⁴, R^(14′) and R¹⁵ are independently selected from H,     halo preferably chloro and fluoro, more preferably fluoro, cyano,     nitro, alkyl preferably methyl, haloalkyl preferably —CF₃ or —CHF₂,     alkoxyalkyl preferably methoxymethyl, alkoxy preferably methoxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, haloalkoxy     preferably OCF₃ or OCHF₂, alkoxyalkoxy preferably 2-methoxyethoxy,     amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl     preferably methylsulfonyl, alkylsulfonylamino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, even more     preferably R¹³, R^(13′), R¹⁴ and R^(14′) are H and R¹⁵ is H, chloro,     methyl or methoxy, methylsulfonyl, methylsulfonylamino, preferably     H, methylsulfonyl, methylsulfonylamino, or R^(13′), R¹⁴, R^(14′) and     R¹⁵ are H and R¹³ is methoxy or chloro, preferably chloro, or R¹³,     R^(13′), R^(14′) and R¹⁵ are H and R¹⁴ is methylsulfonylamino, or     R^(13′), R¹⁴ and R^(14′) are H and R¹³ and R¹⁵ are a) both F, or b)     R¹³ is F and R¹⁵ is methoxy, or c) R¹³ is methoxy and R¹⁵ is F,     or d) R¹³ is methoxy and R¹⁵ is acetylamino, or e) R¹³ is methoxy     and R¹⁵ is amino, or f) R¹³ is cyano and R¹⁵ is methoxy, or g) R¹³     is chloro and R¹⁵ is cyano, or h) R¹³ is cyano and R¹⁵ is     trifluoromethyl, or i) R¹³ is methoxy and R¹⁵ is     (N-methyl-N-methylsulfonyl)amino, or R^(13′), R^(14′) and R¹⁵ are H     and R¹³ and R¹⁴ are a) both methoxy, or b) R¹³ is methyl and R¹⁴ is     methylsulfonylamino, or c) R¹³ is methoxy and R¹⁴ is cyano, or d)     R¹³ is methyl and R¹⁴ is amino, or R¹³, R^(13′) and R^(14′) are H     and R¹⁴ and R¹⁵ are both methoxy, or R^(13′), R¹⁴ and R¹⁵ are H and     R¹³ and R^(14′) are a) both methoxy, or b) R¹⁴ is methoxy and     R^(14′) is cyano, or c) R¹⁴ is methyl and R^(14′) is cyano, or R¹³,     R^(13′) and R¹⁵ are H and R¹⁴ and R^(14′) are both methoxy, or R¹³     and R¹⁴ are H and R^(13′), R^(14′) and R¹⁵ are methoxy, or R¹⁴ and     R¹⁵ are H and R¹³, R^(13′) and R^(14′) are methoxy, or R¹³ and R¹⁴     are methoxy and R^(13′) and R¹⁵ are H and R^(14′) is cyano, or R¹⁴     and R¹⁵ are methoxy and R¹³ and R^(14′) are H and R^(13′) is cyano,     or R¹³ and R¹³⁺ are H and R¹⁴, R^(14′) and R¹⁵ are methoxy.

Preferred compounds of formula Ib-1h are those of formula Ib-1h1

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Ib-1e; -   R¹² is as defined above in respect to formula Ib-1h, preferably R¹²     is H, fluoro, chloro, methyl, CF₃, nitro, cyano, methoxy or     cyclopropylmethyloxy; -   R¹³, R^(13′), R¹⁴, R^(14′) and R¹⁵ are as defined above in respect     to formula Ib-1h, preferably R^(13′), R¹⁴, R^(14′) and R¹⁵ are H and     R¹³ is chloro, cyano, hydroxyl, methyl, trifluoromethyl,     cyanomethyl, methoxy, isopropoxy, isobutyloxy, OCF₃,     cyclopropylmethyloxy, phenoxy, cyclopropylmethyloxy, benzyloxy,     (4-fluorobenzyl)oxy, methoxymethyl, 2-methoxyethoxy,     carbamoylmethyloxy, or R¹³, R^(13′), R^(14′) and R¹⁵ are H and R¹⁴     is chloro, methylsulfonylamino, or R¹³, R^(13′), R¹⁴ and R^(14′) are     H and R¹⁵ is chloro, methylsulfonylamino, R^(13′), R¹⁴ and R^(14′)     are H and R¹³ and R¹⁵ are a) independently selected from chloro or     methoxy, or b) both F, or c) R¹³ is F and R¹⁵ is methoxy, or d) R¹³     is methoxy and R¹⁵ is F, or e) R¹³ is methoxy and R¹⁵ is     acetylamino, or f) R¹³ is methoxy and R¹⁵ is amino, or g) R¹³ is     cyano and R¹⁵ is methoxy, or h) R¹³ is chloro and R¹⁵ is cyano,     or i) R¹³ is cyano and R¹⁵ is trifluoromethyl, or j) R¹³ is methoxy     and R¹⁵ is (N-methyl-N-methylsulfonyl)amino, or R¹⁴, R^(14′) and R¹⁵     are H and both R¹³ and R^(13′) are methoxy, or R¹³, R^(13′) and R¹⁵     are H and both R¹⁴ and R^(14′) are fluoro, methoxy, or R¹³, R^(13′)     and R^(14′) are H and a) R¹⁴ forms together with R¹⁵ a phenyl moiety     fused to the phenyl ring they are attached to, or b) both R¹⁴ and     R¹⁵ are methoxy, or R^(13′), R^(14′) and R¹⁵ are H and R¹³ and R¹⁴     are a) both methoxy, or b) R¹³ is methyl and R¹⁴ is     methylsulfonylamino, or c) R¹³ is methoxy and R¹⁴ is cyano, or d)     R¹³ is methyl and R¹⁴ is amino, or R^(13′), R¹⁴ and R¹⁵ are H and     R¹³ and R^(14′) are a) both methoxy, or b) R¹³ is methoxy and     R^(14′) is cyano, or c) R¹³ is methyl and R^(14′) is cyano, or R¹³     and R¹⁴ are H and R^(13′), R^(14′) and R¹⁵ are methoxy, or R¹⁴ and     R¹⁵ are H and R¹³, R^(13′) and R^(14′) are methoxy, or R¹³ and R¹⁴     are methoxy and R^(13′) and R¹⁵ are H and R^(14′) is cyano, or R¹⁴     and R¹⁵ are methoxy and R¹³ and R^(14′) are H and R^(13′) is cyano,     or R¹³ and R^(13′) are H and R¹⁴, R^(14′) and R¹⁵ are methoxy, more     preferably R^(13′), R¹⁴, R^(14′) and R¹⁵ are H and R¹³ is chloro,     cyano, trifluoromethyl, methoxy, isopropoxy, cyclopropylmethyloxy,     or R¹³, R^(13′), R^(14′) and R¹⁵ are H and R¹⁴ is chloro, or R¹³,     R^(13′), R¹⁴ and R^(14′) are H and R¹⁵ is chloro,     methylsulfonylamino, or R^(13′), R¹⁴ and R^(14′) are H and R¹³ and     R¹⁵ are a) independently selected from chloro or methoxy, or b) both     F, or c) R¹³ is F and R¹⁵ is methoxy, or d) R¹³ is methoxy and R¹⁵     is F, or e) R¹³ is methoxy and R¹⁵ is acetylamino, or f) R¹³ is     methoxy and R¹⁵ is amino, or g) R¹³ is cyano and R¹⁵ is methoxy,     or h) R¹³ is chloro and R¹⁵ is cyano, or i) R¹³ is cyano and R¹⁵ is     trifluoromethyl, or j) R¹³ is methoxy and R¹⁵ is     (N-methyl-N-methylsulfonyl)amino, or R¹⁴, R^(14′) and R¹⁵ are H and     both R¹³ and R^(13′) are methoxy, or R¹³, R^(13′) and R^(14′) are H     and a) R¹⁴ forms together with R¹⁵ a phenyl moiety fused to the     phenyl ring they are attached to, or b) both R¹⁴ and R¹⁵ are     methoxy, or R^(13′), R^(14′) and R¹⁵ are H and R¹³ and R¹⁴ are a)     both methoxy, or b) R¹³ is methyl and R¹⁴ is methylsulfonylamino,     or c) R¹³ is methoxy and R¹⁴ is cyano, or d) R¹³ is methyl and R¹⁴     is amino, or R^(13′), R¹⁴ and R¹⁵ are H and R¹³ and R^(14′) are a)     both methoxy, or b) R¹³ is methoxy and R^(14′) is cyano, or c) R¹³     is methyl and R^(14′) is cyano, or R¹³ and R¹⁴ are H and R^(13′),     R^(14′) and R¹⁵ are methoxy, or R¹⁴ and R¹⁵ are H and R¹³, R^(13′)     and R^(14′) are methoxy, or R¹³ and R¹⁴ methoxy and R^(13′) and R¹⁵     are H and R^(14′) is cyano, or R¹⁴ and R¹⁵ are methoxy and R¹³ and     R^(14′) are H and R^(13′) is cyano, or R¹³ and R^(13′) are H and     R¹⁴, R^(14′) and R¹⁵ are methoxy.

Other preferred compounds of formula Ib-1g are those of formula Ib-1h′

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Ib-1e; -   R¹² is as defined above in respect to formula Ib-1g, preferably R¹²     is H, fluoro, chloro, methyl, CF₃, or methoxy more preferably R¹² is     H or methoxy; -   R¹⁶ is selected from the group of heteroaryl moieties consisting of:

wherein the arrow marks the attachment point to the phenyl ring;

-   R¹⁷, R^(17′), R¹⁸, R^(18′) and R¹⁹ are independently selected from     H, halo preferably chloro and fluoro, cyano, alkyl preferably     methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably     CF₃ or CHF₂, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy,     ethoxy, isopropyloxy, haloalkoxy preferably OCF₃, OCHF₂, or     1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl     preferably methoxymethyl, cycloalkylalkyloxy preferably     cyclopropylmethyloxy, aralkyloxy preferably benzyloxy,     haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl,     alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl,     sulfamoyl, alkylsulfamoyl, alkylsulfonylamino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino,     haloalkylsulfonylamino, preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are     independently selected from H, halo preferably chloro and fluoro,     cyano, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably CF₃, alkoxy preferably methoxy,     ethoxy, isopropyloxy, haloalkoxy preferably OCF₃, OCHF₂, or     1,1,1-trifluoroethyloxy, alkoxyalkyl preferably methoxymethyl,     aralkyloxy preferably benzyloxy, amino, alkylcarbonylamino,     carbamoyl, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl     preferably methylsulfonyl, alkylsulfonylamino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, more     preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected     from H, halo preferably chloro, alkoxy preferably methoxy, even more     preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected     from H, halo preferably chloro, alkoxy preferably methoxy;

Preferred compounds of formula Ib-1h′ are those wherein R¹⁶ is selected from 2-2-methoxypyrimidin-4-yl, 2,4-dibenzyloxypyrimidin-5-yl, 2,4-dimethoxypyrimidin-5-yl, 3,6-dimethoxypyridazin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxypyrimidin-3-yl.

Still other preferred compounds of formula Ib-1g are those of formula Ib-1h″

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R⁸ is F or Cl and R⁹ is H, or both R⁸ and R⁹ are F; -   R is H, methyl, ethyl or tert-butyl; -   A⁰, A^(0′), A¹, A², A³, A⁴ and A⁵ are selected from the combinations     1 to 24:

Combination n^(o) A⁰ A^(0′) A¹ A² A³ A⁴ A⁵ 1 CH CH C—OCH₃ CH C—NHSO₂CH₃ CH CH 2 CH CH C—CH₃ C—NHSO₂CH₃ CH CH CH 3 CH CH C—OCH₃ N CH CH CH 4 CH CH C—OCH₃ N C—OCH₃ N CH 5 C—OCH₃ CH CH N C—OCH₃ N CH 6 CH CH C—OCH₃ N N C—OCH₃ CH 7 CH CH C—OCH₃ CH CH C—CN CH 8 CH CH C—CH₃ CH CH C—CN CH 9 C—F CH C—OCH₃ N N C—OCH₃ CH 10 CH CH CH N CH CH C—OCH₃ 11 CH CH CH CH C—NHSO₂CH₃ CH CH 12 CH CH CH C—NHSO₂CH₃ CH CH CH 13 CH CH CH N C—OCH₃ N C—OCH₃ 14 N C—OCH₃ CH CH CH CH CH 15 CH CH C—OCH₃ N CH N CH 16 CH C—OCH₃ C—OCH₃ CH CH CH CH 17 C—OCH₃ CH CH N CH CH C—OCH₃ 18 C—OCH₃ CH C—OCH₃ N C—OCH₃ N CH 19 CH CH C—OCH₃ CH C—NHCOCH₃ CH CH 20 CH CH C—CN CH C—OCH₃ C—OCH₃ CH 21 CH CH C—OCH₃ CH C—N(CH₃)SO₂CH₃ CH CH 22 N CH C—OCH₃ CH C—OCH₃ CH CH 23 CH CH C—OCH₃ N CH N C—OCH₃ 24 CH CH C—OCH₃ CH N CH CH

Still other preferred compounds of formula Ib-1g are those of formula Ib-1i

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Ib-1f; -   L⁴, R¹¹, R^(11′), R^(12′), R¹³, R^(13′), R¹⁴, R^(14′) and R¹⁵ is as     defined above in respect to formula Ib-1h; -   R¹⁶ is as defined above in respect to formula Ib-1g, preferably R¹⁶     is selected from H, halo preferably chloro or fluoro more preferably     chloro, alkyl, haloalkyl preferably CF₃ or CHF₂, aryl, hydroxyl,     alkoxy, haloalkoxy preferably OCF₃ or OCHF₂, alkoxyalkoxy,     cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl,     haloalkoxyalkyl, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl,     heteroaryloxyalkyl, or R¹⁶ forms together with R^(12′) an     alkylenedioxy group or a haloalkylenedioxy group, each of said     substituents being optionally substituted by one or more further     substituents selected from halo preferably chloro or fluoro, alkoxy,     alkyl, alkylsulfonyl, more preferably R¹⁶ is selected from H, halo     preferably chloro and fluoro more preferably chloro, alkyl,     haloalkyl preferably CF₃ or CHF₂, hydroxyl, alkoxy, haloalkoxy     preferably OCF₃ or OCHF₂, alkoxyalkoxy, haloalkoxyalkyl, or R¹⁶     forms together with R^(12′) an alkylenedioxy group or a     haloalkylenedioxy group, each of said substituents being optionally     substituted by one or more further substituents selected from halo     preferably chloro or fluoro, alkoxy, alkyl, cycloalkyl,     alkylsulfonyl.

Other preferred compounds of formula Ib-1f are those of formula Ib-1j

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect of     formula Ib-1f; -   L⁴ is as defined above in respect to formula Ib-1h, preferably L⁴ is     a single bond; -   R¹¹ and R^(11′) are as defined above in respect to formula Ib-1h,     preferably R¹¹ and R^(11′) are H; -   R^(12′) is as defined above in respect to formula Ib-1h, preferably     R^(12′) is H or methoxy, more preferably R^(12′) is H; -   R¹³, R^(13′), R¹⁴, R^(14′) and R¹⁵ are as defined above in respect     to formula Ib-1h, preferably R^(13′), R¹⁴, R^(14′) and R¹⁵ are H and     R¹³ is chloro, fluoro, methoxy, or R¹³, R^(13′), R^(14′) and R¹⁵ are     H and R¹⁴ is methoxy, or R^(13′), R¹⁴ and R¹⁵ are H and a) both R¹³     and R^(14′) are chloro or b) R¹³ is methoxy and R^(14′) is cyano, or     R^(13′), R¹⁴ and R^(14′) are H and both R¹³ and R¹⁵ are methoxy more     preferably R^(13′), R¹⁴, R^(14′) and R¹⁵ are H and R¹³ is chloro, or     R^(13′), R¹⁴ and R¹⁵ are H and both R¹³ and R^(14′) are chloro.

Other preferred compounds of formula Ib-1f are those of formula Ib-1k

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect of     formula Ib-1e; -   R^(12′) is H, fluoro, chloro, CF₃, methyl or methoxy, preferably     R^(12′) is H or methoxy, more preferably R^(12′) is methoxy; -   R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected from H,     halo preferably chloro and fluoro, more preferably fluoro, cyano,     nitro, alkyl preferably methyl, haloalkyl preferably CF₃ or CHF₂,     alkoxyalkyl preferably methoxymethyl, alkoxy preferably methoxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, haloalkoxy     preferably OCF₃ or OCHF₂, alkoxyalkoxy preferably 2-methoxyethoxy,     amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl     preferably methylsulfonyl, alkylsulfonylamino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, preferably     R^(17′) and R^(18′) are H and both R¹⁷ and R¹⁹ are methoxy.

Other preferred compounds of formula Ib-1f are those of formula Ib-1l

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect of     formula Ib-1e; -   R²⁰ is an aryl or heteroaryl, each of said aryl or heteroaryl being     optionally substituted by one or more substituent(s) selected from     halo, alkyl, haloalkyl, cyano, nitro, phenyl optionally substituted     by one chloro, alkoxy, heterocyclylsulfonyl, alkylsulfamoyl or     alkylsulfonylamino, preferably R²⁰ is a phenyl optionally     substituted by one or more substituent(s) selected from halo     preferably chloro or fluoro, alkyl preferably methyl, haloalkyl     preferably CF₃, cyano, nitro, alkoxy preferably methoxy,     heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl,     (morpholin-4-yl)sulfonyl, alksulfamoyl preferably     diethylaminosulfonyl, alkylsulfonylamino preferably     methylsulfonylamino, or R²⁰ is 4-(4-chlorophenyl)thiazol-2-yl, or     R²⁰ is a benzoxazol-2-yl, more preferably R²⁰ is 2-methoxyphenyl,     2-cyano-4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl,     2-nitro-4-trifluoromethylphenyl, 2-nitro-4-(piperidin-1-yl)sulfonyl     phenyl, 4-(morpholin-4-yl)sulfonylphenyl,     2-nitro-4-diethylaminosulfonyl phenyl, 2-nitro-4-tolyl,     2-cyano-4-nitrophenyl, 4-nitrophenyl, 2-fluoro-4-nitrophenyl,     3-methoxy-4-nitrophenyl, 5-chloro-2-nitrophenyl,     2-cyano-4-methylsulfonylaminophenyl, 2-cyano-4-methoxyphenyl,     2-methylsulfonylamino-4-trifluoromethylphenyl, 2-nitrophenyl,     4-cyanophenyl, 2-methoxy-4-trifluoromethylphenyl, or R²⁰ is     4-(4-chlorophenyl)thiazol-2-yl, or R²⁰ is a benzoxazol-2-yl, even     more preferably R²⁰ is 2-cyano-4-trifluoromethylphenyl,     2-nitro-4-trifluoromethylphenyl, 2-methoxy-4-trifluoromethylphenyl.

Other preferred compounds of formula Ib are those of formula Ib-2

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar¹, Ar², R¹, R², R³, R^(3′), R⁴, R^(4′), L², L³, D, E and Z are as     defined above in respect of formula Ib; and -   the bond represented by the dotted line is either absent or present.     Preferred compounds of formula Ib-2 and pharmaceutically acceptable     salts, solvates and prodrugs thereof are those wherein the dotted     line is absent.

Further preferred compounds of formula Ib are those of formula Ib-3

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar¹, Ar², R¹, R², R³, R^(3′), R⁴, R^(4′), L¹, L², D and E are as     defined above in respect of formula Ib, -   R is as defined above in respect of formula I; and -   the bond represented by the dotted line is either absent or present.     Preferred compounds of formula Ib-3 and pharmaceutically acceptable     salts, solvates and prodrugs thereof are those wherein dotted line     is absent.

Yet other preferred compounds of formula Ib are those of formula Ib-4

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar¹, Ar², R¹, R², L¹, L², L³, D, E and Z are as defined above in     respect of formula Ib; and -   the bond represented by the dotted line is either absent or present.     Preferred compounds of formula Ib-4 and pharmaceutically acceptable     salts, solvates and prodrugs thereof are those wherein the dotted     line is absent.

Further preferred compounds of formula Ib are those of formula Ib-5

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar¹, Ar², L¹, L³, R¹, R², R³, R^(3′), R⁴, R^(4′) and Z are as     defined above in respect of formula Ib; and -   the bond represented by the dotted line is either absent or present.     Preferred compounds of formula Ib-5 and pharmaceutically acceptable     salts, solvates and prodrugs thereof are those wherein the dotted     line is absent.

Further preferred compounds of formula Ib are those of formula Ib-6

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar¹, Ar², L¹, L², L³, R³, R^(3′), R⁴, R^(4′), D, E and Z are as     defined above in respect of formula Ib; and -   the bond represented by the dotted line is either absent or present.     Preferred compounds of formula Ib-6 and pharmaceutically acceptable     salts, solvates and prodrugs thereof are those wherein the dotted     line is absent.

In yet another embodiment, preferred compounds of Formula I are those of formula Ic:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar¹, Ar², L¹, L², L³, R¹, R², R³, R^(3′), R⁴, R^(4′), D, E and Z are     as defined above in respect of formula I; and -   the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Ic and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein the dotted line is absent.

Other preferred compounds of formula Ic are those of formula Ic-1b′:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R² is as defined above in respect of formula Ic and R is as defined     above in respect of formula I; -   R¹ is H; -   D is C═O; -   L² is single bond; -   Ar¹ is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-membered     cycloalkyl group, or a linear or branched C₃-C₆ alkyl group, each of     which being optionally substituted by one or more group(s) selected     from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl,     hydroxyl, alkoxy, haloalkoxy, amino, alkylamino, carboxy,     alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,     haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino, or two substituents form an alkylenedioxy     group or a haloalkylenedioxy group, each of said aryl or heteroaryl     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl,     alkoxy, haloalkoxy, preferably Ar¹ is a 5- to 6-membered aryl     preferably phenyl, 5- to 6-membered heteroaryl group preferably     pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl,     isobutyl or isopentyl each of said phenyl, pyridin-2-yl,     pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally     substituted by one or more group(s) selected from halo preferably     bromo, chloro or fluoro, cyano, C₁-C₄ alkyl preferably methyl, C₁-C₄     alkoxy preferably methoxy, aryl preferably phenyl, still more     preferably Ar¹ is aryl preferably phenyl, cyclohexyl, isobutyl or     isopentyl, said phenyl group being optionally substituted by one or     more halo group preferably bromo, chloro or fluoro, cyano, methyl,     phenyl or methoxy, further more preferably Ar¹ is phenyl,     cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl,     3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,     4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2-cyanophenyl,     3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, 1,1′-biphenyl-2-yl, 4-cyanophenyl, even more     preferably Ar¹ is isobutyl, cyclohexyl, phenyl, 2-chlorophenyl,     2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl,     2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, still even more preferably Ar¹ is isobutyl,     2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl,     2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl; -   Ar² is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C₂-C₆     alkyl group, each of which being optionally substituted by one or     more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl,     cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl,     heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl     heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy,     alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,     aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, amino,     alkylamino, arylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl,     heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy,     heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl,     alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl,     alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, oxo,     or two substituents form an alkylenedioxy group or a     haloalkylenedioxy group, or fused to the aryl, heteroaryl,     cycloalkyl or heterocyclyl group may be one or more aryl or     heteroaryl moiety, each of said substituents being optionally     substituted by one or more further substituents selected from halo,     cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl,     cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or     methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy,     alkoxyalkyl, alkoxyalkoxy, haloalkoxy, cycloalkyloxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by a     fluoro or alkyl or cycloalkyl group, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, amino, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl,     arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino, oxo, alkoxyalkoxy, alkoxyalkyl, and     haloalkoxyalkyl; preferably Ar² is an aryl or heteroaryl preferably     pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C₂-C₆ alkyl group,     each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl     groups being optionally substituted by one or more group(s) selected     from halo preferably chloro and fluoro, cyano, nitro, alkyl,     haloalkyl preferably CF₃ or CHF₂, heterocyclyl, aryl, aralkyl,     heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably     OCF₃ or OCHF₂, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy,     heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl,     heteroaryloxyalkyl, arylcarbonyl, or two substituents form an     alkylenedioxy group or a haloalkylenedioxy group, or fused to the     cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of     said substituents being optionally substituted by one or more     further substituents selected from halo preferably chloro or fluoro,     cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably CF₃, cyanomethyl, alkoxy preferably     methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by     one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino,     carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino,     still more preferably Ar² is an aryl preferably phenyl, heteroaryl     preferably pyridyl, heterocyclyl preferably piperidinyl, C₂-C₆ alkyl     group preferably isobutyl, each of said aryl, heteroaryl and     heterocyclyl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro and fluoro, cyano,     nitro, alkyl, preferably methyl, heterocyclyl preferably     pyrrolidin-1-yl, 4-methylpiperidin-1-yl, aryl preferably phenyl,     heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl,     pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy,     alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy,     phenethyloxy or 3,3-diphenylpropan-1-oxy, heteroarylalkyloxy     preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl     preferably phenoxymethyl, heteroaryloxyalkyl preferably     pyridinyloxymethyl, arylcarbonyl preferably phenyl acetyl, or two     substituents form an haloalkylenedioxy group each of said     substituents being optionally substituted by one or more further     substituents selected from halo preferably chloro or fluoro, more     preferably fluoro, cyano, nitro, alkyl preferably methyl,     cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl     preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy,     aryloxy preferably phenoxy, aralkyloxy optionally substituted by one     fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino,     alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably     methylsulfonylalkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, further more preferably Ar² is a     biaryl consisting of two 6-membered aryl moieties preferably     biphenyl, more preferably a biphenyl linked to L² at position 4′ and     monosubstituted at position 2, or Ar² is a heterobiaryl consisting     of one 6-membered aryl moiety and one 6-membered heteroaryl moiety     or two 6-membered heteroaryl moieties, said heterobiaryl being     linked to L² either on the aryl or on the heteroaryl moiety and     being preferably phenylpyridyl, pyrimidinylphenyl,     pyridazinylphenyl, pyrazinylphenyl, or Ar² is an aryl or heteroaryl     optionally substituted by one group selected from arylalkyloxy,     aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl     and heteroaryl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, cyano,     nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy     optionally substituted by one fluoro preferably benzyloxy or     4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino,     alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, or Ar² is a piperidinyl ring     linked to L² at position 4 and N substituted with a phenyl,     4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said     phenyl moiety being further substituted by one or more substituents     selected from halo preferably chloro and fluoro, cyano, nitro, alkyl     preferably methyl, haloalkyl preferably CF₃, alkoxy preferably     methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl,     (morpholin-4-yl)sulfonyl, alksulfamoyl preferably     methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar²     is 4′-(2-methoxy-1,1′-biphenyl), 4′-(2-methyl-1,1′-biphenyl),     4′-(2-fluoro-1,1′-biphenyl), 4′-(4-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl), 4′-(2-chloro-2′-methoxy-1,1′-biphenyl),     4′-(2-(2-methoxyethoxy)-1,1′-biphenyl),     4′-(2-(methoxymethyl)-1,1′-biphenyl), 4′-(4-methoxy-1,1′-biphenyl),     4′-(4-cyano-1,1′-biphenyl), 4′-(3-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl),     4′-(4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-trifluoromethoxy-1,1′-biphenyl),     4′-(2-isopropoxy-1,1′-biphenyl),     4′-(2-cyclopropylmethyloxy-1,1′-biphenyl),     4′-(2-cyano-1,1′-biphenyl), 4′-(2,6-dimethoxy-1,1′-biphenyl),     4′-(2,4-dichloro-1,1′-biphenyl),     4′-(2-trifluoromethyl-1,1′-biphenyl),     4′-(2-methoxy-4-chloro-1,1′-biphenyl),     4′-(2,4-dimethoxy-1,1′-biphenyl), 4-(2,2′-dimethoxy-1,1′-biphenyl),     4-(naphtalen-2-yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl,     4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl,     4-(2-methoxypyridin-3-yl)phenyl,     4-(2,6-dimethoxy-pyridin-3-yl)phenyl,     4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl,     4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl,     4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl,     4-(2,4-dimethoxypyrimidin-6-yl)phenyl,     4-(2,4-dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl,     4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl,     (4-phenoxymethyl)phenyl, optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, more     preferably fluoro, alkyl preferably methyl, alkoxy preferably     methoxy, or Ar² is 4′-(2,4-difluoro-1,1′-biphenyl),     4′-(3′-methyl-1,1′-biphenyl), 4′-(3′-fluoro-1,1′-biphenyl),     4′-(2-fluoro-4-methoxy-1,1′-biphenyl),     4′-(4-fluoro-2-methoxy-1,1′-biphenyl),     4′-(2,3-dimethoxy-1,1′-biphenyl), 4′-(3,4-dimethoxy-1,1′-biphenyl),     4′-(2,3,4-trimethoxy-1,1′-biphenyl),     4′-(2,3,6-trimethoxy-1,1′-biphenyl),     4′-(3,5-dimethoxy-1,1′-biphenyl), 4′-(2,5-dimethoxy-1,1′-biphenyl),     4′-(2-isopropyl-1,1′-biphenyl), 4′-(2,2′-dimethoxy-1,1′-biphenyl),     4′-(2′-fluoro,2-dimethoxy-1,1′-biphenyl),     4′-(2-ethyl-1,1′-biphenyl), 4′-(4-propyl-1,1′-biphenyl),     4′-(4-tert-butyl-1,1′-biphenyl),     4′-(2-methoxy-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methoxy-4-acetylamino-1,1′-biphenyl),     4′-(3-hydroxycarbamimidoyl-1,1′-biphenyl), 4′-(4-amino-2-meth     oxy-1,1′-biphenyl), 4′-(3-carbamoyl-1,1′-biphenyl),     4′-(5-cyano-2,3-dimethoxy-1,1′-biphenyl),     4′-(2-cyano-4,5-dimethoxy-1,1′-biphenyl),     4′-(3,4,5-trimethoxy-1,1′-biphenyl), 4′-(2-cyano     methyl-4,5-dimethoxy-1,1′-biphenyl),     4′-(2-fluoro-5-cyano-1,1′-biphenyl),     4′-(2′-fluoro-3,4-dimethoxy-1,1′-biphenyl),     4′-(3-carbamoyl-4-cyano-1,1′-biphenyl),     4′-(2-cyano-4-methoxy-1,1′-biphenyl),     4′-(2′-fluoro-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2′-fluoro-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-cyano-2′-fluoro-1,1′-biphenyl),     4′-(2-chloro-5-cyano-1,1′-biphenyl),     4′-(2-cyano-4-trifluoromethyl-1,1′-biphenyl),     4′-(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(4-methylsulfonyl-1,1′-biphenyl),     4′-(3-methylsulfonylamino-1,1′-biphenyl),     4′-(4-amino-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methoxy-1,1′-biphenyl), 4′-(3-cyano-1,1′-biphenyl),     4′-(2-cyano-3-methoxy-1,1′-biphenyl),     4′-(2-methyl-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methyl-3-acetylamino-1,1′-biphenyl),     4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl,     4-(2-ethoxypyridin-5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl,     4-(2-methoxy-6-methylpyridin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl,     4-(2,6-dimethylpyridin-5-yl)phenyl,     4-(2,6-dimethoxy-pyrimidin-5-yl)-3-chlorophenyl,     4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl,     4-(4,6-dimethoxy-pyridin-3-yl)phenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)phenyl,     4-(2,6-dimethoxy-pyridin-3-yl)phenyl,     4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(2,6-dimethoxy-pyridin-3-yl)-3-fluorophenyl,     4-(6-methoxy-pyridin-3-yl)-3-fluorophenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl,     dimethoxy-pyrimidin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-5-yl)-3-methoxyphenyl,     4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3-yl)phenyl,     4-(2-methoxy-pyrimidin-3-yl)phenyl,     3-methoxy-2-(2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(5-cyano-2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl,     2-(2,4-dimethoxyphenyl)pyridin-5-yl,     1-(2-cyano-4-trifluoromethyl)piperidin-4-yl,     1-(2-nitro-4-trifluoromethyl)piperidin-4-yl,     1-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; -   R³ is H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl,     arylsulfonyl; -   R^(3′) is H or C₁-C₄ alkyl; -   R⁴ is H, cyano, C₁-C₄ alkyl.

Preferred compounds of formula Ic-1b′ are those of formula Ic-1g:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are independently selected from H,     halo preferably fluoro, chloro, bromo, cyano, alkyl, hydroxyalkyl,     haloalkyl preferably CF₃ or CHF₂, cycloalkyl, cycloalkylalkyl,     heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably     phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, haloalkoxy     preferably OCF₃ or OCHF₂, heterocyclyloxy, alkylamino,     alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl,     aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy,     cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy,     heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino, hetero     arylcarbonylamino, alkylcarbonylamino alkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of     R⁸ and R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′) and R^(8′)     form an alkylenedioxy group or a haloalkylenedioxy group together     with the phenyl group they are attached to, or one or more of R⁸ and     R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′) and R^(8′) form     together a cycloalkyl, aryl, heterocycloalyl or heteroaryl moiety     fused to the phenyl group they are attached to, each of said     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, hydroxyalkyl,     haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl,     alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy,     alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino or oxo, preferably R⁸, R^(8′), R⁹, R^(9′) and     R¹⁰ are independently selected from H, halo preferably fluoro,     chloro, bromo, cyano, alkyl, haloalkyl preferably CF₃ or CHF₂,     cycloalkyl, aryl preferably phenyl, heteroaryl, hydroxyl, haloalkoxy     preferably OCF₃ or OCHF₂, alkylamino, alkoxycarbonyl,     alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or one     or more of R⁸ and R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′)     and R^(8′) form an alkylenedioxy group or a haloalkylenedioxy group     together with the phenyl group they are attached to, each of said     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl,     alkoxy, haloalkoxy, more preferably R⁸, R^(8′), R⁹, R^(9′) and R¹⁰     are independently selected from H, halo preferably bromo, fluoro or     chloro, cyano, C₁-C₄ alkyl preferably methyl, aryl preferably     phenyl, alkoxy preferably methoxy, still more preferably R⁸, R^(8′),     R⁹, R^(9′) and R¹⁰ are independently selected from H, halo     preferably bromo, fluoro or chloro, alkyl preferably methyl, still     more preferably R⁸ is Br, Cl or F, preferably Cl and R^(8′), R⁹,     R^(9′) and R¹⁰ are independently selected from H or F, or R⁹ is Cl     or F and R⁸, R^(8′), R^(9′) and R¹⁰ are H, or R⁹ and R^(9′) are F     and R⁸, R^(8′) and R¹⁰ are H, or R¹⁰ is Cl or F and R⁸, R^(8′), R⁹     and R^(9′) are H, even more preferably R⁸ is Br, Cl or F and R^(8′),     R⁹, R^(9′) and R¹⁰ are H, or R⁸ and R⁹ are F and R^(8′), R^(9′) and     R¹⁰ are H, or R⁸ and R¹⁰ are F and R^(8′), R⁹ and R^(9′) are H; -   R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from     H, halo preferably chloro and fluoro more preferably chloro, cyano,     nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl,     cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl,     aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl,     alkoxy, haloalkoxy preferably —OCF₃ or —OCHF₂, alkoxyalkoxy,     cycloalkyloxy, heterocyclyloxy, aryloxy, hetero aryloxy,     alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl,     alkyloxycarbonyl, aminoalkylalkoxycarbonyl, cycloalkyloxycarbonyl,     heterocyclyloxy carbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy,     arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of     R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and     R^(11′) form an alkylenedioxy group or a haloalkylenedioxy group     together with the phenyl group they are attached to, or one or more     of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and     R^(11′) form together a cycloalkyl, aryl, heterocycloalkyl or     heteroaryl moiety fused to the phenyl group they are attached to,     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,     cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted     by one a chloro or methyl group, heteroaryl, cycloalkylalkyl,     aralkyl, heteroarylalkyl, heteroalkyl, hydroxyl, alkoxy,     alkoxyalkoxy, haloalkoxy preferably trifluoromethoxy,     1,1,1-trifluoroethyloxy, alkoxyalkyl, haloalkoxyalkyl,     cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy,     aryloxy, aralkyloxy optionally substituted by one fluoro, amino,     alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,     cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy     preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably     phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, haloalkylsulfonylamino and oxo, preferably     R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are, independently selected from     H, halo preferably chloro and fluoro more preferably chloro, cyano,     nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl,     cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl,     aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl,     alkoxy, haloalkoxy preferably —OCF₃ or —OCHF₂, alkoxyalkoxy,     cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl,     haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl,     alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy,     alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, or one or more of R¹¹ and R¹², or R¹² and     R¹⁶, or R¹⁶ and R¹², or R^(12′) and R^(11′) form an alkylenedioxy     group or a haloalkylenedioxy group together with the phenyl group     they are attached to, or one or more of R¹¹ and R¹², or R¹² and R¹⁶,     or R¹⁶ and R^(12′), or R¹² and R^(11′) form together an aryl or     heteroaryl moiety fused to the phenyl group they are attached to,     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,     cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted     by one a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl,     alkoxy, alkoxyalkoxy, haloalkoxy preferably 1,1,1-trifluoroethyloxy,     alkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably     cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by     one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino,     alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl     preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl,     alkylsulfonylamino, haloalkylsulfonylamino and oxo, more preferably     R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from     H, halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl     preferably CF₃ or CHF₂, heterocyclyl, aryl, aralkyl, heteroaryl,     heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF₃ or     OCHF₂, alkoxyalkoxy, aryloxy, cycloalkylalkyloxy, arylalkyloxy,     heteroarylalkyloxy, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl,     arylcarbonyl, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶     and R^(12′), or R^(12′) and R^(11′) form an alkylenedioxy group or a     haloalkylenedioxy group together with the phenyl group they are     attached to, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶     and R^(12′), or R^(12′) and R^(11′) form together an aryl, or     heteroaryl moiety fused to the phenyl group they are attached to,     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, cyanomethyl, cycloalkyl, heterocyclyl, alkoxy preferably     methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by     one fluoro, amino, alkylamino, alkylcarbonylamino, carbamoyl,     hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more     preferably R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently     selected from H, halo preferably chloro and fluoro, cyano, nitro,     alkyl preferably methyl, ethyl, isopropyl or isobutyl, haloalkyl     preferably CF₃ or CHF₂, cycloalkyl preferably cyclohexyl,     heterocyclyl preferably pyrrolidin-1-yl, 4-methylpiperidin-1-yl,     aryl preferably phenyl, heteroaryl preferably thiophenyl, pyridinyl,     pyrimidinyl, pyrazinyl, pyridazinyl, aralkyl preferably benzyl,     alkoxy preferably methoxy, ethoxy or isopropyloxy,     cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy     or 3,3-diphenylpropan-1-oxy, heteroarylalkyloxy preferably     pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably     phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, or     two substituents form an haloalkylenedioxy group each of said     substituents being optionally substituted by one or more further     substituents selected from halo preferably chloro or fluoro, cyano,     alkyl preferably methyl, haloalkyl preferably trifluoromethyl,     alkoxy preferably methoxy, isopropyloxy, isobutyloxy, alkoxyalkyl     preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy     preferably phenoxy, aralkyloxy optionally substituted by one fluoro,     preferably benzyloxy, 4-fluorobenzyloxy, amino, alkylcarbonylamino     preferably acetylamino, alkylsulfonyl preferably methylsulfonyl,     alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino.

Preferred compounds of formula Ic-1g are those of formula Ic-1h1:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Ic-1g; -   R¹² is as defined above in respect to formula Ic-1g, preferably R¹²     is H, fluoro, chloro, methyl, CF₃, nitro, cyano, methoxy or     cyclopropylmethyloxy; -   R¹³, R^(13′), R¹⁴, R^(14′) and R¹⁵ are as defined above in respect     to formula Ic-1g, preferably R^(13′), R¹⁴, R^(14′) and R¹⁵ are H and     R¹³ is chloro, cyano, hydroxyl, methyl, trifluoromethyl,     cyanomethyl, methoxy, isopropoxy, isobutyloxy, OCF₃,     cyclopropylmethyloxy, phenoxy, cyclopropylmethyloxy, benzyloxy,     (4-fluorobenzyl)oxy, methoxymethyl, 2-methoxyethoxy,     carbamoylmethyloxy, or R¹³, R^(13′), R^(14′) and R¹⁵ are H and R¹⁴     is chloro, methylsulfonylamino, or R¹³, R^(13′), R¹⁴ and R^(14′) are     H and R¹⁵ is chloro, methylsulfonylamino, R^(13′), R¹⁴ and R^(14′)     are H and R¹³ and R¹⁵ are a) independently selected from chloro or     methoxy, or b) both F, or c) R¹³ is F and R¹⁵ is methoxy, or d) R¹³     is methoxy and R¹⁵ is F, or e) R¹³ is methoxy and R¹⁵ is     acetylamino, or f) R¹³ is methoxy and R¹⁵ is amino, or g) R¹³ is     cyano and R¹⁵ is methoxy, or h) R¹³ is chloro and R¹⁵ is cyano,     or i) R¹³ is cyano and R¹⁵ is trifluoromethyl, or j) R¹³ is methoxy     and R¹⁵ is (N-methyl-N-methylsulfonyl)amino, or R¹⁴, R^(14′) and R¹⁵     are H and both R¹⁴ and R^(14′) are methoxy, or R¹³, R^(13′) and R¹⁵     are H and both R¹⁴ and R^(14′) are fluoro, methoxy, or R¹³, R^(13′)     and R^(14′) are H and a) R¹⁴ forms together with R¹⁵ a phenyl moiety     fused to the phenyl ring they are attached to, or b) both R¹⁴ and     R¹⁵ are methoxy, or R^(13′), R^(14′) and R¹⁵ are H and R¹³ and R¹⁴     are a) both methoxy, or b) R¹³ is methyl and R¹⁴ is     methylsulfonylamino, or c) R¹³ is methoxy and R¹⁴ is cyano, or d)     R¹³ is methyl and R¹⁴ is amino, or R^(13′), R¹⁴ and R¹⁵ are H and     R¹³ and R^(14′) are a) both methoxy, or b) R¹³ is methoxy and     R^(14′) is cyano, or c) R¹³ is methyl and R^(14′) is cyano, or R¹³     and R¹⁴ are H and R^(13′), R^(14′) and R¹⁵ are methoxy, or R¹⁴ and     R¹⁵ are H and R¹³, R^(13′) and R^(14′) are methoxy, or R¹³ and R¹⁴     are methoxy and R^(13′) and R¹⁵ are H and R^(14′) is cyano, or R¹⁴     and R¹⁵ are methoxy and R¹³ and R^(14′) are H and R^(13′) is cyano,     or R¹³ and R^(13′) are H and R¹⁴, R^(14′) and R¹⁵ are methoxy, more     preferably R^(13′), R¹⁴, R^(14′) and R¹⁵ are H and R¹³ is chloro,     cyano, trifluoromethyl, methoxy, isopropoxy, cyclopropylmethyloxy,     or R¹³, R^(14′) and R¹⁵ are H and R¹⁴ is chloro, or R¹³, R^(13′),     R¹⁴ and R^(14′) are H and R¹⁵ is chloro, methylsulfonylamino, or     R^(13′), R¹⁴ and R^(14′) are H and R¹³ and R¹⁵ are a) independently     selected from chloro or methoxy, or b) both F, or c) R¹³ is F and     R¹⁵ is methoxy, or d) R¹³ is methoxy and R¹⁵ is F, or e) R¹³ is     methoxy and R¹⁵ is acetylamino, or f) R¹³ is methoxy and R¹⁵ is     amino, or g) R¹³ is cyano and R¹⁵ is methoxy, or h) R¹³ is chloro     and R¹⁵ is cyano, or i) R¹³ is cyano and R¹⁵ is trifluoromethyl,     or j) R¹³ is methoxy and R¹⁵ is (N-methyl-N-methylsulfonyl)amino, or     R¹⁴, R^(14′) and R¹⁵ are H and both R¹³ and R^(13′) are methoxy, or     R¹³, R^(13′) and R^(14′) are H and a) R¹⁴ forms together with R¹⁵ a     phenyl moiety fused to the phenyl ring they are attached to, or b)     both R¹⁴ and R¹⁵ are methoxy, or R^(13′), R^(14′) and R¹⁵ are H and     R¹³ and R¹⁴ are a) both methoxy, or b) R¹³ is methyl and R¹⁴ is     methylsulfonylamino, or c) R¹³ is methoxy and R¹⁴ is cyano, or d)     R¹³ is methyl and R¹⁴ is amino, or R^(13′), R¹⁴ and R¹⁵ are H and     R¹³ and R^(14′) are a) both methoxy, or h) R¹³ is methoxy and     R^(14′) is cyano, or c) R¹³ is methyl and R^(14′) is cyano, or R¹³     and R¹⁴ are H and R^(13′), R^(14′) and R¹⁵ are methoxy, or R¹⁴ and     R¹⁵ are H and R¹³, R^(13′) and R^(14′) are methoxy, or R¹³ and R¹⁴     are methoxy and R^(13′) and R¹⁵ are H and R^(14′) is cyano, or R¹⁴     and R¹⁵ are methoxy and R¹³ and R^(14′) are H and R^(13′) is cyano,     or R¹³ and R^(13′) are H and R¹⁴, R^(14′) and R¹⁵ are methoxy.

Other preferred compounds of formula Ic-1g are those of formula Ic-1h′:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Ic-1g; -   R¹² is as defined above in respect to formula Ic-1g, preferably R¹²     is H, fluoro, chloro, methyl, CF₃, or methoxy more preferably R¹² is     H or methoxy; -   R¹⁶ is selected from the group of heteroaryl moieties consisting of:

wherein the arrow marks the attachment point to the phenyl ring;

-   R¹⁷, R^(17′), R¹⁸, R^(18′) and R¹⁹ are independently selected from     H, halo preferably chloro and fluoro, cyano, alkyl preferably     methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably     CF₃ or CHF₂, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy,     ethoxy, isopropyloxy, haloalkoxy preferably OCF₃, OCHF₂, or     1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl     preferably methoxymethyl, cycloalkylalkyloxy preferably     cyclopropylmethyloxy, aralkyloxy preferably benzyloxy,     haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl,     alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl,     sulfamoyl, alkylsulfamoyl, alkylsulfonylamino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino,     haloalkylsulfonylamino, preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are     independently selected from H, halo preferably chloro and fluoro,     cyano, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably CF₃, alkoxy preferably methoxy,     ethoxy, isopropyloxy, haloalkoxy preferably OCF₃, OCHF₂, or     1,1,1-trifluoroethyloxy, alkoxyalkyl preferably methoxymethyl,     aralkyloxy preferably benzyloxy, amino, alkylcarbonylamino,     carbamoyl, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl     preferably methylsulfonyl, alkyl sulfonyl amino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, more     preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected     from H, halo preferably chloro, alkoxy preferably methoxy, even more     preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected     from H, halo preferably chloro, alkoxy preferably methoxy;

Preferred compounds of formula Ic-1h′ are those wherein R¹⁶ is selected from 2-2-methoxypyrimidin-4-yl, 2,4-dibenzyloxypyrimidin-5-yl, 2,4-dimethoxypyrimidin-5-yl, 3,6-dimethoxypyridazin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxypyrimidin-3-yl.

In yet another embodiment, preferred compounds of Formula I are those of formula Id:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   Ar¹, Ar², L¹, L², L³, R¹, R², R³, R^(3′), R⁴, R^(4′), D, E and Z are     as defined above in respect of formula I; and     the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Id and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein the dotted line is absent.

Other preferred compounds of formula Id are those of formula Id-1b′:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R² is as defined above in respect of formula Id and R is as defined     above in respect of formula I; -   R¹ is H; -   D is C═O; -   L² is single bond; -   Ar¹ is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-membered     cycloalkyl group, or a linear or branched C₃-C₆ alkyl group, each of     which being optionally substituted by one or more group(s) selected     from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl,     hydroxyl, alkoxy, haloalkoxy, amino, alkylamino, carboxy,     alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,     haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino, or two substituents form an alkylenedioxy     group or a haloalkylenedioxy group, each of said aryl or heteroaryl     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl,     alkoxy, haloalkoxy, preferably Ar¹ is a 5- to 6-membered aryl     preferably phenyl, 5- to 6-membered heteroaryl group preferably     pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl,     isobutyl or isopentyl each of said phenyl, pyridin-2-yl,     pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally     substituted by one or more group(s) selected from halo preferably     bromo, chloro or fluoro, cyano, C₁-C₄ alkyl preferably methyl, C₁-C₄     alkoxy preferably methoxy, aryl preferably phenyl, still more     preferably Ar¹ is aryl preferably phenyl, cyclohexyl, isobutyl or     isopentyl, said phenyl group being optionally substituted by one or     more halo group preferably bromo, chloro or fluoro, cyano, methyl,     phenyl or methoxy, further more preferably Ar¹ is phenyl,     cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl,     3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,     4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2-cyanophenyl,     3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, 1,1′-biphenyl-2-yl, 4-cyanophenyl, even more     preferably Ar¹ is isobutyl, cyclohexyl, phenyl, 2-chlorophenyl,     2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl,     2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, still even more preferably Ar¹ is isobutyl,     2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl,     2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl; -   Ar² is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C₂-C₆     alkyl group, each of which being optionally substituted by one or     more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl,     cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl,     heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl     heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy,     alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,     aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, amino,     alkylamino, arylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl,     heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy,     heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl,     alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl,     alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, oxo,     or two substituents form an alkylenedioxy group or a     haloalkylenedioxy group, or fused to the aryl, heteroaryl,     cycloalkyl or heterocyclyl group may be one or more aryl or     heteroaryl moiety, each of said substituents being optionally     substituted by one or more further substituents selected from halo,     cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl,     cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or     methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy,     alkoxyalkyl, alkoxyalkoxy, haloalkoxy, cycloalkyloxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by a     fluoro or alkyl or cycloalkyl group, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, amino, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl,     arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino, oxo, alkoxyalkoxy, alkoxyalkyl, and     haloalkoxyalkyl; preferably Ar² is an aryl or heteroaryl preferably     pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C₂-C₆ alkyl group,     each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl     groups being optionally substituted by one or more group(s) selected     from halo preferably chloro and fluoro, cyano, nitro, alkyl,     haloalkyl preferably CF₃ or CHF₂, heterocyclyl, aryl, aralkyl,     heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably     OCF₃ or OCHF₂, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy,     heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl,     heteroaryloxyalkyl, arylcarbonyl, or two substituents form an     alkylenedioxy group or a haloalkylenedioxy group, or fused to the     cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of     said substituents being optionally substituted by one or more     further substituents selected from halo preferably chloro or fluoro,     cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably CF₃, cyanomethyl, alkoxy preferably     methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy,     cycloalkylalkyloxy, aryloxy, aralkyl oxy optionally substituted by     one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino,     carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino,     still more preferably Ar² is an aryl preferably phenyl, heteroaryl     preferably pyridyl, heterocyclyl preferably piperidinyl, C₂-C₆ alkyl     group preferably isobutyl, each of said aryl, heteroaryl and     heterocyclyl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro and fluoro, cyano,     nitro, alkyl, preferably methyl, heterocyclyl preferably     pyrrolidin-1-yl, 4-methylpiperidin-1-yl, aryl preferably phenyl,     heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl,     pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy,     alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy,     phenethyloxy or 3,3-diphenylpropan-1-oxy, heteroarylalkyloxy     preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl     preferably phenoxymethyl, heteroaryloxyalkyl preferably     pyridinyloxymethyl, arylcarbonyl preferably phenylacetyl, or two     substituents form an haloalkylenedioxy group each of said     substituents being optionally substituted by one or more further     substituents selected from halo preferably chloro or fluoro, more     preferably fluoro, cyano, nitro, alkyl preferably methyl,     cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl     preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy,     aryloxy preferably phenoxy, aralkyloxy optionally substituted by one     fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino,     alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably     methylsulfonylalkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, further more preferably Ar² is a     biaryl consisting of two 6-membered aryl moieties preferably     biphenyl, more preferably a biphenyl linked to L² at position 4′ and     monosubstituted at position 2, or Ar² is a heterobiaryl consisting     of one 6-membered aryl moiety and one 6-membered heteroaryl moiety     or two 6-membered heteroaryl moieties, said heterobiaryl being     linked to L² either on the aryl or on the heteroaryl moiety and     being preferably phenylpyridyl, pyrimidinylphenyl,     pyridazinylphenyl, pyrazinylphenyl, or Ar² is an aryl or heteroaryl     optionally substituted by one group selected from arylalkyloxy,     aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl     and heteroaryl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, cyano,     nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy     optionally substituted by one fluoro preferably benzyloxy or     4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino,     alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, or Ar² is a piperidinyl ring     linked to L² at position 4 and N substituted with a phenyl,     4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said     phenyl moiety being further substituted by one or more substituents     selected from halo preferably chloro and fluoro, cyano, nitro, alkyl     preferably methyl, haloalkyl preferably CF₃, alkoxy preferably     methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl,     (morpholin-4-yl)sulfonyl, alksulfamoyl preferably     methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar²     is 4′-(2-methoxy-1,1′-biphenyl), 4′-(2-methyl-1,1′-biphenyl),     4′-(2-fluoro-1,1′-biphenyl), 4′-(4-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl), 4′-(2-chloro-2′-methoxy-1,1′-biphenyl),     4′-(2-(2-methoxyethoxy)-1,1′-biphenyl),     4′-(2-(methoxymethyl)-1,1′-biphenyl), 4′-(4-methoxy-1,1′-biphenyl),     4′-(4-cyano-1,1′-biphenyl), 4′-(3-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl),     4′-(4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-trifluoromethoxy-1,1′-biphenyl),     4′-(2-isopropoxy-1,1′-biphenyl),     4′-(2-cyclopropylmethyloxy-1,1′-biphenyl),     4′-(2-cyano-1,1′-biphenyl), 4′-(2,6-dimethoxy-1,1′-biphenyl),     4′-(2,4-dichloro-1,1′-biphenyl),     4′-(2-trifluoromethyl-1,1′-biphenyl),     4′-(2-methoxy-4-chloro-1,1′-biphenyl),     4′-(2,4-dimethoxy-1,1′-biphenyl), 4-(2,2′-dimethoxy-1,1′-biphenyl),     4-(naphtalen-2-yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl,     4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl,     4-(2-methoxypyridin-3-yl)phenyl, dimethoxy-pyridin-3-yl)phenyl,     4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl,     4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl,     4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl,     4-(2,4-dimethoxypyrimidin-6-yl)phenyl,     4-(2,4-dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl,     4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl,     (4-phenoxymethyl)phenyl, optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, more     preferably fluoro, alkyl preferably methyl, alkoxy preferably     methoxy, or Ar² is 4′-(2,4-difluoro-1,1′-biphenyl),     4′-(3′-methyl-1,1′-biphenyl), 4′-(3′-fluoro-1,1′-biphenyl),     4′-(2-fluoro-4-methoxy-1,1′-biphenyl),     4′-(4-fluoro-2-methoxy-1,1′-biphenyl),     4′-(2,3-dimethoxy-1,1′-biphenyl), 4′-(3,4-dimethoxy-1,1′-biphenyl),     4′-(2,3,4-trimethoxy-1,1′-biphenyl),     4′-(2,3,6-trimethoxy-1,1′-biphenyl),     4′-(3,5-dimethoxy-1,1′-biphenyl), 4′-(2,5-dimethoxy-1,1′-biphenyl),     4′-(2-isopropyl-1,1′-biphenyl), 4′-(2,2′-dimethoxy-1,1′-biphenyl),     4′-(2′-fluoro,2-dimethoxy-1,1′-biphenyl),     4′-(2-ethyl-1,1′-biphenyl), 4′-(4-propyl-1,1′-biphenyl),     4′-(4-tert-butyl-1,1′-biphenyl),     4′-(2-methoxy-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methoxy-4-acetylamino-1,1′-biphenyl),     4′-(3-hydroxycarbamimidoyl-1,1′-biphenyl),     4′-(4-amino-2-methoxy-1,1′-biphenyl),     4′-(3-carbamoyl-1,1′-biphenyl),     4′-(5-cyano-2,3-dimethoxy-1,1′-biphenyl),     4′-(2-cyano-4,5-dimethoxy-1,1′-biphenyl),     4′-(3,4,5-trimethoxy-1,1′-biphenyl),     4′-(2-cyanomethyl-4,5-dimethoxy-1,1′-biphenyl),     4′-(2-fluoro-5-cyano-1,1′-biphenyl),     4′-(2′-fluoro-3,4-dimethoxy-1,1′-biphenyl),     4′-(3-carbamoyl-4-cyano-1,1′-biphenyl),     4′-(2-cyano-4-methoxy-1,1′-biphenyl),     4′-(2′-fluoro-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2′-fluoro-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-cyano-2′-fluoro-1,1′-biphenyl),     4′-(2-chloro-5-cyano-1,1′-biphenyl),     4′-(2-cyano-4-trifluoromethyl-1,1′-biphenyl),     4′-(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(4-methylsulfonyl-1,1′-biphenyl),     4′-(3-methylsulfonylamino-1,1′-biphenyl),     4′-(4-amino-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methoxy-1,1′-biphenyl), 4′-(3-cyano-1,1′-biphenyl),     4′-(2-cyano-3-methoxy-1,1′-biphenyl),     4′-(2-methyl-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methyl-3-acetylamino-1,1′-biphenyl),     4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl,     4-(2-ethoxypyridin-5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl,     4-(2-methoxy-6-methylpyridin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl,     4-(2,6-dimethylpyridin-5-yl)phenyl,     4-(2,6-dimethoxy-pyrimidin-5-yl)-3-chlorophenyl,     4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl,     4-(4,6-dimethoxy-pyridin-3-yl)phenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)phenyl,     4-(2,6-dimethoxy-pyridin-3-yl)phenyl,     4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(2,6-dimethoxy-pyridin-3-yl)-3-fluorophenyl,     4-(6-methoxy-pyridin-3-yl)-3-fluorophenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl,     dimethoxy-pyrimidin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-5-yl)-3-methoxyphenyl,     4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3-yl)phenyl,     4-(2-methoxy-pyrimidin-3-yl)phenyl,     3-methoxy-2-(2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(5-cyano-2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl,     2-(2,4-dimethoxyphenyl)pyridin-5-yl,     1-(2-cyano-4-trifluoromethyl)piperidin-4-yl,     1-(2-nitro-4-trifluoromethyl)piperidin-4-yl,     1-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; -   R³ is H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl,     arylsulfonyl; -   R^(3′) is H or C₁-C₄ alkyl; -   R⁴ is H, cyano, C₁-C₄ alkyl.

Preferred compounds of formula Id-1b′ are those of formula Id-1g:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are independently selected from H,     halo preferably fluoro, chloro, bromo, cyano, alkyl, hydroxyalkyl,     haloalkyl preferably CF₃ or CHF₂, cycloalkyl, cycloalkylalkyl,     heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably     phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, haloalkoxy     preferably OCF₃ or OCHF₂, heterocyclyloxy, alkylamino,     alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl,     aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy,     cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy,     heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylamino alkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of     R⁸ and R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′) and R^(8′)     form an alkylenedioxy group or a haloalkylenedioxy group together     with the phenyl group they are attached to, or one or more of R⁸ and     R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′) and R^(8′) form     together a cycloalkyl, aryl, heterocycloalyl or heteroaryl moiety     fused to the phenyl group they are attached to, each of said     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, hydroxyalkyl,     haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl,     alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy,     alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino,     alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino or oxo, preferably R⁸, R^(8′), R⁹, R^(9′) and     R¹⁰ are independently selected from H, halo preferably fluoro,     chloro, bromo, cyano, alkyl, haloalkyl preferably CF₃ or CHF₂,     cycloalkyl, aryl preferably phenyl, heteroaryl, hydroxyl, haloalkoxy     preferably OCF₃ or OCHF₂, alkylamino, alkoxycarbonyl,     alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or one     or more of R⁸ and R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′)     and R^(8′) form an alkylenedioxy group or a haloalkylenedioxy group     together with the phenyl group they are attached to, each of said     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl,     alkoxy, haloalkoxy, more preferably R⁸, R^(8′), R⁹, R^(9′) and R¹⁰     are independently selected from H, halo preferably bromo, fluoro or     chloro, cyano, C₁-C₄ alkyl preferably methyl, aryl preferably     phenyl, alkoxy preferably methoxy, still more preferably R⁸, R^(8′),     R⁹, R^(9′) and R¹⁰ are independently selected from H, halo     preferably bromo, fluoro or chloro, alkyl preferably methyl, still     more preferably R⁸ is Br, Cl or F, preferably Cl and R^(8′), R⁹,     R^(9′), and R¹⁰ are independently selected from H or F, or R⁹ is Cl     or F and R⁸, R^(8′), R^(9′) and R¹⁰ are H, or R⁹ and R^(9′) are F     and R⁸, R^(8′) and R¹⁰ are H, or R¹⁰ is Cl or F and R⁸, R^(8′), R⁹     and R^(9′) are H, even more preferably R⁸ is Br, Cl or F and R^(8′),     R⁹, R^(9′) and R¹⁰ are H, or R⁸ and R⁹ are F and R^(8′), R^(9′) and     R¹⁰ are H, or R⁸ and R¹⁰ are F and R^(8′), R⁹ and R^(9′) are H; -   R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from     H, halo preferably chloro and fluoro more preferably chloro, cyano,     nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl,     cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl,     aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl,     alkoxy, haloalkoxy preferably —OCF₃ or —OCHF₂, alkoxyalkoxy,     cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl,     haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl,     alkyloxycarbonyl, aminoalkylalkoxycarbonyl, cycloalkyloxycarbonyl,     heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy,     arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of     R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and     R^(11′) form an alkylenedioxy group or a haloalkylenedioxy group     together with the phenyl group they are attached to, or one or more     of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and     R^(11′) form together a cycloalkyl, aryl, heterocycloalkyl or     heteroaryl moiety fused to the phenyl group they are attached to,     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,     cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted     by one a chloro or methyl group, heteroaryl, cycloalkylalkyl,     aralkyl, heteroarylalkyl, heteroalkyl, hydroxyl, alkoxy,     alkoxyalkoxy, haloalkoxy preferably trifluoromethoxy,     1,1,1-trifluoroethyloxy, alkoxyalkyl, haloalkoxyalkyl,     cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy,     aryloxy, aralkyloxy optionally substituted by one fluoro, amino,     alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,     cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy     preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoyl amino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably     phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     cycloalkylsulfonylamino, haloalkylsulfonylamino and oxo, preferably     R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from     H, halo preferably chloro and fluoro more preferably chloro, cyano,     nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl,     cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl,     aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl,     alkoxy, haloalkoxy preferably —OCF₃ or —OCHF₂, alkoxyalkoxy,     cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl,     haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl,     alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,     alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy,     alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl,     heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, or one or more of R¹¹ and R¹², or R¹² and     R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form an     alkylenedioxy group or a haloalkylenedioxy group together with the     phenyl group they are attached to, or one or more of R¹¹ and R¹², or     R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form     together an aryl or heteroaryl moiety fused to the phenyl group they     are attached to, each of said substituents being optionally     substituted by one or more further substituents selected from halo     preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl,     alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl     optionally substituted by one a chloro or methyl group, heteroaryl,     heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably     1,1,1-trifluoroethyloxy, alkoxyalkyl, cycloalkyloxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy,     aralkyloxy optionally substituted by one fluoro, amino, alkylamino,     carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy,     alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy preferably     carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably     phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino and oxo, more preferably R¹¹, R^(11′), R¹²,     R^(12′) and R¹⁶ are independently selected from H, halo preferably     chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF₃ or     CHF₂, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,     hydroxyl, alkoxy, haloalkoxy preferably OCF₃ or OCHF₂, alkoxyalkoxy,     aryloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy,     alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or one     or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or     R^(12′) and R^(11′) form an alkylenedioxy group or a     haloalkylenedioxy group together with the phenyl group they are     attached to, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶     and R^(12′), or R^(12′) and R^(11′) form together an aryl, or     heteroaryl moiety fused to the phenyl group they are attached to,     each of said substituents being optionally substituted by one or     more further substituents selected from halo preferably chloro or     fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, cyanomethyl, cycloalkyl, heterocyclyl, alkoxy preferably     methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by     one fluoro, amino, alkylamino, alkylcarbonylamino, carbamoyl,     hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more     preferably R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently     selected from H, halo preferably chloro and fluoro, cyano, nitro,     alkyl preferably methyl, ethyl, isopropyl or isobutyl, haloalkyl     preferably CF₃ or CHF₂, cycloalkyl preferably cyclohexyl,     heterocyclyl preferably pyrrolidin-1-yl, 4-methylpiperidin-1-yl,     aryl preferably phenyl, heteroaryl preferably thiophenyl, pyridinyl,     pyrimidinyl, pyrazinyl, pyridazinyl, aralkyl preferably benzyl,     alkoxy preferably methoxy, ethoxy or isopropyloxy,     cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy     or 3,3-diphenylpropan-1-oxy, heteroarylalkyloxy preferably     pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably     phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, or     two substituents form an haloalkylenedioxy group each of said     substituents being optionally substituted by one or more further     substituents selected from halo preferably chloro or fluoro, cyano,     alkyl preferably methyl, haloalkyl preferably trifluoromethyl,     alkoxy preferably methoxy, isopropyloxy, isobutyloxy, alkoxyalkyl     preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy     preferably phenoxy, aralkyloxy optionally substituted by one fluoro,     preferably benzyloxy, 4-fluorobenzyloxy, amino, alkylcarbonylamino     preferably acetyl amino, alkylsulfonyl preferably methylsulfonyl,     alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino.

Preferred compounds of formula Id-1g are those of formula Id-1h1:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Id-1g; -   R¹² is as defined above in respect to formula Id-1g, preferably R¹²     is H, fluoro, chloro, methyl, CF₃, nitro, cyano, methoxy or     cyclopropylmethyloxy; -   R¹³, R^(13′), R¹⁴, R^(14′) and R¹⁵ are as defined above in respect     to formula Id-1g, preferably R^(13′), R¹⁴, R^(14′), and R¹⁵ are H     and R¹³ is chloro, cyano, hydroxyl, methyl, trifluoromethyl,     cyanomethyl, methoxy, isopropoxy, isobutyloxy, OCF₃,     cyclopropylmethyloxy, phenoxy, cyclopropylmethyloxy, benzyloxy,     (4-fluorobenzyl)oxy, methoxymethyl, 2-methoxyethoxy,     carbamoylmethyloxy, or R¹³, R^(13′), R^(14′) and R¹⁵ are H and R¹⁴     is chloro, methylsulfonylamino, or R¹³, R^(13′), R¹⁴ and R^(14′) are     H and R¹⁵ is chloro, methylsulfonylamino, R^(13′), R¹⁴ and R^(14′)     are H and R¹³ and R¹⁵ are a) independently selected from chloro or     methoxy, or b) both F, or c) R¹³ is F and R¹⁵ is methoxy, or d) R¹³     is methoxy and R¹⁵ is F, or e) R¹³ is methoxy and R¹⁵ is     acetylamino, or f) R¹³ is methoxy and R¹⁵ is amino, or g) R¹³ is     cyano and R¹⁵ is methoxy, or h) 11¹³ is chloro and R¹⁵ is cyano,     or i) R¹³ is cyano and R¹⁵ is trifluoromethyl, or j) R¹³ is methoxy     and R¹⁵ is (N-methyl-N-methylsulfonyl)amino, or R¹⁴, R^(14′) and R¹⁵     are H and both R¹³ and R^(13′) are methoxy, or R¹³, R^(13′) and R¹⁵     are H and both R¹⁴ and R^(14′) are fluoro, methoxy, or R¹³, R^(13′)     and R^(14′) are H and a) R¹⁴ forms together with R¹⁵ a phenyl moiety     fused to the phenyl ring they are attached to, or b) both R¹⁴ and     R¹⁵ are methoxy, or R^(13′), R^(14′) and R¹⁵ are H and R¹³ and R¹⁴     are a) both methoxy, or b) R¹³ is methyl and R¹⁴ is     methylsulfonylamino, or c) R¹³ is methoxy and R¹⁴ is cyano, or d)     R¹³ is methyl and R¹⁴ is amino, or R^(13′), R¹⁴ and R¹⁵ are H and     R¹³ and R^(14′) are a) both methoxy, or b) R¹³ is methoxy and     R^(14′) is cyano, or c) R¹³ is methyl and R^(14′) is cyano, or R¹³     and R¹⁴ are H and R^(13′), R^(14′) and R¹⁵ are methoxy, or R¹⁴ and     R¹⁵ are H and R¹³, R^(13′) and R^(14′) are methoxy, or R¹³ and R¹⁴     are methoxy and R^(13′) and R¹⁵ are H and R^(14′) is cyano, or R¹⁴     and R¹⁵ are methoxy and R¹³ and R^(14′) are H and R^(13′) is cyano,     or R¹³ and R^(13′) are H and R¹⁴, R^(14′) and R¹⁵ are methoxy, more     preferably R^(13′), R¹⁴, R^(14′) and R¹⁵ are H and R¹³ is chloro,     cyano, trifluoromethyl, methoxy, isopropoxy, cyclopropylmethyloxy,     or R¹³, R^(13′), R^(14′) and R¹⁵ are H and R¹⁴ is chloro, or R¹³,     R^(13′), R¹⁴ and R^(14′) are H and R¹⁵ is chloro,     methylsulfonylamino, or R^(13′), R¹⁴ and R^(14′) are H and R¹³ and     R¹⁵ are a) independently selected from chloro or methoxy, or b) both     F, or c) R¹³ is F and R¹⁵ is methoxy, or d) R¹³ is methoxy and R¹⁵     is F, or e) R¹³ is methoxy and R¹⁵ is acetylamino, or f) R¹³ is     methoxy and R¹⁵ is amino, or g) R¹³ is cyano and R¹⁵ is methoxy,     or h) R¹³ is chloro and R¹⁵ is cyano, or i) R¹³ is cyano and R¹⁵ is     trifluoromethyl, or j) R¹³ is methoxy and R¹⁵ is     (N-methyl-N-methylsulfonyl)amino, or R¹⁴, R^(14′) and R¹⁵ are H and     both R¹³ and R^(13′) are methoxy, or R¹³, R^(13′) and R^(14′) are H     and a) R¹⁴ forms together with R¹⁵ a phenyl moiety fused to the     phenyl ring they are attached to, or b) both R¹⁴ and R¹⁵ are     methoxy, or R^(13′), R^(14′) and R¹⁵ are H and R¹³ and R¹⁴ are a)     both methoxy, or b) R¹³ is methyl and R¹⁴ is methylsulfonylamino,     or c) R¹³ is methoxy and R¹⁴ is cyano, or d) R¹³ is methyl and R¹⁴     is amino, or R^(13′), R¹⁴ and R¹⁵ are H and R¹³ and R^(14′) are a)     both methoxy, or h) R¹³ is methoxy and R^(14′) is cyano, or c) R¹³     is methyl and R^(14′) is cyano, or R¹³ and R¹⁴ are H and R^(13′),     R^(14′) and R¹⁵ are methoxy, or R¹⁴ and R¹⁵ are H and R¹³, R^(13′)     and R^(14′) are methoxy, or R¹³ and R¹⁴ are methoxy and R^(13′) and     R¹⁵ are H and R^(14′) is cyano, or R¹⁴ and R¹⁵ are methoxy and R¹³     and R^(14′) are H and R^(13′) is cyano, or R¹³ and R^(13′) are H and     R¹⁴, R^(14′) and R¹⁵ are methoxy.

Other preferred compounds of formula Id-1g are those of formula Id-1h′:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Id-1g; -   R¹² is as defined above in respect to formula Id-1g, preferably R¹²     is H, fluoro, chloro, methyl, CF₃, or methoxy more preferably R¹² is     H or methoxy; -   R¹⁶ is selected from the group of heteroaryl moieties consisting of:

wherein the arrow marks the attachment point to the phenyl ring;

-   R¹⁷, R^(17′), R¹⁸, R^(18′) and R¹⁹ are independently selected from     H, halo preferably chloro and fluoro, cyano, alkyl preferably     methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably     CF₃ or CHF₂, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy,     ethoxy, isopropyloxy, haloalkoxy preferably OCF₃, OCHF₂, or     1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl     preferably methoxymethyl, cycloalkylalkyloxy preferably     cyclopropylmethyloxy, aralkyloxy preferably benzyloxy,     haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl,     alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl,     sulfamoyl, alkylsulfamoyl, alkylsulfonylamino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino,     haloalkylsulfonylamino, preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are     independently selected from H, halo preferably chloro and fluoro,     cyano, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably CF₃, alkoxy preferably methoxy,     ethoxy, isopropyloxy, haloalkoxy preferably OCF₃, OCHF₂, or     1,1,1-trifluoroethyloxy, alkoxyalkyl preferably methoxymethyl,     aralkyloxy preferably benzyloxy, amino, alkylcarbonylamino,     carbamoyl, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl     preferably methylsulfonyl, alkyl sulfonyl amino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, more     preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected     from H, halo preferably chloro, alkoxy preferably methoxy, even more     preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected     from H, halo preferably chloro, alkoxy preferably methoxy;

Preferred compounds of formula Id-1h′ are those wherein R¹⁶ is selected from 2-2-methoxypyrimidin-4-yl, 2,4-dibenzyloxypyrimidin-5-yl, 2,4-dimethoxypyrimidin-5-yl, 3,6-dimethoxypyridazin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxypyrimidin-3-yl.

In yet another embodiment, preferred compounds of Formula I are those of formula Ie:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

Ar¹, Ar², L¹, L², L³, R¹, R², R³, R^(3′), R⁴, R^(4′), D, E and Z are as defined above in respect of formula I; and

-   the bond represented by the dotted line is either absent or present.

Preferred compounds of formula Ie and pharmaceutically acceptable salts, solvates and prodrugs thereof are those wherein the dotted line is absent.

Other preferred compounds of formula Ie are those of formula Ie-1b′:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R² is as defined above in respect of formula Ie and R is as defined     above in respect of formula I; -   R¹ is H; -   D is C═O; -   L² is single bond; -   Ar¹ is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-membered     cycloalkyl group, or a linear or branched C₃-C₆ alkyl group, each of     which being optionally substituted by one or more group(s) selected     from halo, cyano, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl,     hydroxyl, alkoxy, haloalkoxy, amino, alkylamino, carboxy,     alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,     haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino, or two substituents form an alkylenedioxy     group or a haloalkylenedioxy group, each of said aryl or heteroaryl     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl,     alkoxy, haloalkoxy, preferably Ar¹ is a 5- to 6-membered aryl     preferably phenyl, 5- to 6-membered heteroaryl group preferably     pyridin-2-yl, pyridin-3-yl, cyclohexyl, cyclopentyl, isopropyl,     isobutyl or isopentyl each of said phenyl, pyridin-2-yl,     pyridin-3-yl, cyclohexyl or cyclopentyl group being optionally     substituted by one or more group(s) selected from halo preferably     bromo, chloro or fluoro, cyano, C₁-C₄ alkyl preferably methyl, C₁-C₄     alkoxy preferably methoxy, aryl preferably phenyl, still more     preferably Ar¹ is aryl preferably phenyl, cyclohexyl, isobutyl or     isopentyl, said phenyl group being optionally substituted by one or     more halo group preferably bromo, chloro or fluoro, cyano, methyl,     phenyl or methoxy, further more preferably Ar¹ is phenyl,     cyclohexyl, isobutyl, 2-chlorophenyl, 2-tolyl, 2-methoxyphenyl,     3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,     4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2-cyanophenyl,     3,5-difluorophenyl, 3,4-difluorophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, 1,1′-biphenyl-2-yl, 4-cyanophenyl, even more     preferably Ar¹ is isobutyl, cyclohexyl, phenyl, 2-chlorophenyl,     2-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl,     2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,     2,4-dichlorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl, still even more preferably Ar¹ is isobutyl,     2-chlorophenyl, 2-tolyl, 2-methoxyphenyl, 2-fluorophenyl,     2,4-difluorophenyl, 2-bromophenyl, 2,3-difluorophenyl,     2,5-difluorophenyl; -   Ar² is an aryl or heteroaryl, cycloalkyl, heterocyclyl or C₂-C₆     alkyl group, each of which being optionally substituted by one or     more group(s) selected from halo, cyano, nitro, alkyl, haloalkyl,     cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl,     heterocyclylalkyl, aryl, aralkyl, heteroaryl, benzoxazol-2-yl     heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy,     alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,     aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, arylalkyloxy,     heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, amino,     alkylamino, arylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl,     heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy,     heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl,     alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl,     alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, oxo,     or two substituents form an alkylenedioxy group or a     haloalkylenedioxy group, or fused to the aryl, heteroaryl,     cycloalkyl or heterocyclyl group may be one or more aryl or     heteroaryl moiety, each of said substituents being optionally     substituted by one or more further substituents selected from halo,     cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, cyanomethyl,     cycloalkyl, heterocyclyl, aryl optionally substituted by a chloro or     methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy,     alkoxyalkyl, alkoxyalkoxy, haloalkoxy, cycloalkyloxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by a     fluoro or alkyl or cycloalkyl group, carboxy, alkoxycarbonyl,     alkylcarbonyloxy, amino, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl,     carbamoylalkyloxy, carbamoylamino, alkylcarbamoylamino,     carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl,     haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl,     arylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,     haloalkylsulfonylamino, oxo, alkoxyalkoxy, alkoxyalkyl, and     haloalkoxyalkyl; preferably Ar² is an aryl or heteroaryl preferably     pyridyl, pyrazinyl, cycloalkyl, heterocyclyl or C₂-C₆ alkyl group,     each of each of said aryl, heteroaryl, cycloalkyl and heterocyclyl     groups being optionally substituted by one or more group(s) selected     from halo preferably chloro and fluoro, cyano, nitro, alkyl,     haloalkyl preferably CF₃ or CHF₂, heterocyclyl, aryl, aralkyl,     heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably     OCF₃ or OCHF₂, alkoxyalkoxy, aryloxy, alkoxyalkyl, arylalkyloxy,     heteroarylalkyloxy, cycloalkylalkyloxy, aryloxyalkyl,     heteroaryloxyalkyl, arylcarbonyl, or two substituents form an     alkylenedioxy group or a haloalkylenedioxy group, or fused to the     cycloalkyl or heterocycloalkyl group may be one aryl moiety, each of     said substituents being optionally substituted by one or more     further substituents selected from halo preferably chloro or fluoro,     cyano, nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably CF₃, cyanomethyl, alkoxy preferably     methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy,     cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by     one fluoro or alkyl or cycloalkyl, amino, alkylcarbonylamino,     carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino,     still more preferably Ar² is an aryl preferably phenyl, heteroaryl     preferably pyridyl, heterocyclyl preferably piperidinyl, C₂-C₆ alkyl     group preferably isobutyl, each of said aryl, heteroaryl and     heterocyclyl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro and fluoro, cyano,     nitro, alkyl, preferably methyl, heterocyclyl preferably     pyrrolidin-1-yl, 4-methylpiperidin-1-yl, aryl preferably phenyl,     heteroaryl preferably pyridinyl, pyrimidinyl, pyrazinyl,     pyridazinyl, alkoxy preferably methoxy, ethoxy or isopropyloxy,     alkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy,     phenethyloxy or 3,3-diphenylpropan-1-oxy, heteroarylalkyloxy     preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl     preferably phenoxymethyl, heteroaryloxyalkyl preferably     pyridinyloxymethyl, arylcarbonyl preferably phenylacetyl, or two     substituents form an haloalkylenedioxy group each of said     substituents being optionally substituted by one or more further     substituents selected from halo preferably chloro or fluoro, more     preferably fluoro, cyano, nitro, alkyl preferably methyl,     cycloalkyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy preferably cyclopropylmethyloxy, alkoxyalkyl     preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy,     aryloxy preferably phenoxy, aralkyloxy optionally substituted by one     fluoro, preferably benzyloxy or 4-fluorobenzyloxy, amino,     alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably     methylsulfonylalkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, further more preferably Ar² is a     biaryl consisting of two 6-membered aryl moieties preferably     biphenyl, more preferably a biphenyl linked to L² at position 4′ and     monosubstituted at position 2, or Ar² is a heterobiaryl consisting     of one 6-membered aryl moiety and one 6-membered heteroaryl moiety     or two 6-membered heteroaryl moieties, said heterobiaryl being     linked to L² either on the aryl or on the heteroaryl moiety and     being preferably phenylpyridyl, pyrimidinylphenyl,     pyridazinylphenyl, pyrazinylphenyl, or Ar² is an aryl or heteroaryl     optionally substituted by one group selected from arylalkyloxy,     aryloxyalkyl, arylcarbonyl, each of said biaryl, heterobiaryl, aryl     and heteroaryl groups being optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, cyano,     nitro, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy,     cycloalkylalkyloxy, aryloxy preferably phenoxy, aralkyloxy     optionally substituted by one fluoro preferably benzyloxy or     4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino,     alkylsulfonylamino preferably methylsulfonylamino,     (N-methyl-N-methylsulfonyl)amino, or Ar² is a piperidinyl ring     linked to L² at position 4 and N substituted with a phenyl,     4-(4-chlorophenyl)thiazol-2-yl or benzoxazol-2-yl moiety, said     phenyl moiety being further substituted by one or more substituents     selected from halo preferably chloro and fluoro, cyano, nitro, alkyl     preferably methyl, haloalkyl preferably CF₃, alkoxy preferably     methoxy, heterocyclylsulfonyl preferably (piperidin-1-yl)sulfonyl,     (morpholin-4-yl)sulfonyl, alksulfamoyl preferably     methylsulfonylamino, diethylaminosulfonyl, even more preferably Ar²     is 4′-(2-methoxy-1,1′-biphenyl), 4′-(2-methyl-1,1′-biphenyl),     4′-(2-fluoro-1,1′-biphenyl), 4′-(4-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl), 4′-(2-chloro-2′-methoxy-1,1′-biphenyl),     4′-(2-(2-methoxyethoxy)-1,1′-biphenyl),     4′-(2-(methoxymethyl)-1,1′-biphenyl), 4′-(4-methoxy-1,1′-biphenyl),     4′-(4-cyano-1,1′-biphenyl), 4′-(3-chloro-1,1′-biphenyl),     4′-(2-chloro-1,1′-biphenyl),     4′-(4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-trifluoromethoxy-1,1′-biphenyl),     4′-(2-isopropoxy-1,1′-biphenyl),     4′-(2-cyclopropylmethyloxy-1,1′-biphenyl),     4′-(2-cyano-1,1′-biphenyl), 4′-(2,6-dimethoxy-1,1′-biphenyl),     4′-(2,4-dichloro-1,1′-biphenyl),     4′-(2-trifluoromethyl-1,1′-biphenyl),     4′-(2-methoxy-4-chloro-1,1′-biphenyl),     4′-(2,4-dimethoxy-1,1′-biphenyl), 4-(2,2′-dimethoxy-1,1′-biphenyl),     4-(naphtalen-2-yl)phenyl, 5-(2-phenyl)pyridyl, 4-cyclohexylphenyl,     4-benzylphenyl, 4-(3-thienyl)phenyl, 4-(pyridin-3-yl)phenyl,     4-(2-methoxypyridin-3-yl)phenyl,     4-(2,6-dimethoxy-pyridin-3-yl)phenyl,     4-(2-(2-methoxyethoxy)-pyridin-3-yl)phenyl,     4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl,     4-(2-methoxypyrimidin-5-yl)-3-methoxyphenyl,     4-(2,4-dimethoxypyrimidin-6-yl)phenyl,     4-(2,4-dimethoxypyrimidin-5-yl)phenyl, (4-benzyloxy)phenyl,     4-phenoxyphenyl, (3-phenethyloxy)phenyl, (4-phenethyloxy)phenyl,     (4-phenoxymethyl)phenyl, optionally substituted by one or more     group(s) selected from halo preferably chloro or fluoro, more     preferably fluoro, alkyl preferably methyl, alkoxy preferably     methoxy, or Ar² is 4′-(2,4-difluoro-1,1′-biphenyl),     4′-(3′-methyl-1,1′-biphenyl), 4′-(3′-fluoro-1,1′-biphenyl),     4′-(2-fluoro-4-methoxy-1,1′-biphenyl),     4′-(4-fluoro-2-methoxy-1,1′-biphenyl),     4′-(2,3-dimethoxy-1,1′-biphenyl), 4′-(3,4-dimethoxy-1,1′-biphenyl),     4′-(2,3,4-trimethoxy-1,1′-biphenyl),     4′-(2,3,6-trimethoxy-1,1′-biphenyl),     4′-(3,5-dimethoxy-1,1′-biphenyl), 4′-(2,5-dimethoxy-1,1′-biphenyl),     4′-(2-isopropyl-1,1′-biphenyl), 4′-(2,2′-dimethoxy-1,1′-biphenyl),     4′-(2′-fluoro,2-dimethoxy-1,1′-biphenyl),     4′-(2-ethyl-1,1′-biphenyl), 4′-(4-propyl-1,1′-biphenyl),     4′-(4-tert-butyl-1,1′-biphenyl),     4′-(2-methoxy-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methoxy-4-acetylamino-1,11-biphenyl),     4′-(3-hydroxycarbamimidoyl-1,1′-biphenyl),     4′-(4-amino-2-methoxy-1,1′-biphenyl),     4′-(3-carbamoyl-1,1′-biphenyl),     4′-(5-cyano-2,3-dimethoxy-1,1′-biphenyl),     4′-(2-cyano-4,5-dimethoxy-1,1′-biphenyl),     4′-(3,4,5-trimethoxy-1,1′-biphenyl), 4′-(2-cyano     methyl-4,5-dimethoxy-1,1′-biphenyl),     4′-(2-fluoro-5-cyano-1,1′-biphenyl),     4′-(2′-fluoro-3,4-dimethoxy-1,1′-biphenyl),     4′-(3-carbamoyl-4-cyano-1,1′-biphenyl),     4′-(2-cyano-4-methoxy-1,1′-biphenyl),     4′-(2′-fluoro-4-methylsulfonylamino-1,1′-biphenyl),     4′-(2′-fluoro-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-cyano-2′-fluoro-1,1′-biphenyl),     4′-(2-chloro-5-cyano-1,1′-biphenyl),     4′-(2-cyano-4-trifluoromethyl-1,1′-biphenyl),     4′-(2-methyl-3-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(2-methyl-4-(N-methyl-N-methylsulfonyl)amino-1,1′-biphenyl),     4′-(4-methylsulfonyl-1,1′-biphenyl),     4′-(3-methylsulfonylamino-1,1′-biphenyl),     4′-(4-amino-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methyl-1,1′-biphenyl),     4′-(5-cyano-2-methoxy-1,1′-biphenyl), 4′-(3-cyano-1,1′-biphenyl),     4′-(2-cyano-3-methoxy-1,1′-biphenyl),     4′-(2-methyl-3-methylsulfonylamino-1,1′-biphenyl),     4′-(2-methyl-3-acetylamino-1,1′-biphenyl),     4-(2-chloro-6-methoxypyrimidin-5-yl)phenyl,     4-(2-ethoxypyridin-5-yl)phenyl, 4-(2-isopropoxypyridin-5-yl)phenyl,     4-(2-meth oxy-6-methylpyridin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-4-yl)-3-chlorophenyl,     4-(2,6-dimethylpyridin-5-yl)phenyl,     4-(2,6-dimethoxy-pyrimidin-5-yl)-3-chlorophenyl,     4-(4-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(6-methoxy-pyridin-3-yl)-3-chlorophenyl,     4-(4,6-dimethoxy-pyridin-3-yl)phenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)phenyl,     4-(2,6-dimethoxy-pyridin-3-yl)phenyl,     4-(5-methoxy-pyridin-3-yl)-3-methoxyphenyl,     4-(2,6-dimethoxy-pyridin-3-yl)-3-fluorophenyl,     4-(6-methoxy-pyridin-3-yl)-3-fluorophenyl,     4-(3,6-dimethoxy-pyridazin-5-yl)-3-fluorophenyl,     dimethoxy-pyrimidin-5-yl)phenyl,     4-(2-methoxy-pyrimidin-5-yl)-3-methoxyphenyl,     4-(3-methoxy-pyridin-4-yl)phenyl, 4-(4-methoxy-pyridin-3-yl)phenyl,     4-(2-methoxy-pyrimidin-3-yl)phenyl,     3-methoxy-2-(2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(5-cyano-2-methoxyphenyl)pyridin-5-yl,     3-methoxy-2-(2,4-dimethoxyphenyl)pyridin-5-yl,     2-(2,4-dimethoxyphenyl)pyridin-5-yl,     1-(2-cyano-4-trifluoromethyl)piperidin-4-yl,     1-(2-nitro-4-trifluoromethyl)piperidin-4-yl,     1-(2-methoxy-4-trifluoromethyl)piperidin-4-yl; -   R³ is H, cyano, alkyl, hydroxyalkyl, aralkyl, alkoxyalkyl, acetyl,     arylsulfonyl; -   R^(3′) is H or C₁-C₄ alkyl; -   R⁴ is H, cyano, C₁-C₄ alkyl.

Preferred compounds of formula Ie-1b′ are those of formula Ie-1g:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect of formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are independently selected from H,     halo preferably fluoro, chloro, bromo, cyano, alkyl, hydroxyalkyl,     haloalkyl preferably CF₃ or CHF₂, cycloalkyl, cycloalkylalkyl,     heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl preferably     phenyl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, haloalkoxy     preferably OCF₃ or OCHF₂, heterocyclyloxy, alkylamino,     alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl,     aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy,     cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy,     heteroarylcarbonyloxy, arylalkyloxy, alkylcarbonylamino,     haloalkylcarbonylamino, cycloalkylcarbonylamino,     heterocyclylcarbonylamino arylcarbonylamino,     heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl,     heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,     cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl,     heteroarylsulfonyl sulfamoyl, alkylsulfamoyl, arylsulfamoyl,     heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     heterocyclylsulfonylamino, arylsulfonylamino,     heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of     R⁸ and R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′) and R^(8′)     form an alkylenedioxy group or a haloalkylenedioxy group together     with the phenyl group they are attached to, or one or more of R⁸ and     R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′) and R^(8′) form     together a cycloalkyl, aryl, heterocycloalyl or heteroaryl moiety     fused to the phenyl group they are attached to, each of said     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, hydroxyalkyl,     haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyl,     alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy,     alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy,     alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonyl     amino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl,     alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,     alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino,     haloalkylsulfonylamino or oxo, preferably R⁸, R^(8′), R⁹, R^(9′) and     R¹⁰ are independently selected from H, halo preferably fluoro,     chloro, bromo, cyano, alkyl, haloalkyl preferably CF₃ or CHF₂,     cycloalkyl, aryl preferably phenyl, heteroaryl, hydroxyl, haloalkoxy     preferably OCF₃ or OCHF₂, alkylamino, alkoxycarbonyl,     alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino,     carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl,     alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or one     or more of R⁸ and R⁹, or R⁹ and R¹⁰, or R¹⁰ and R^(9′), or R^(9′)     and R^(8′) form an alkylenedioxy group or a haloalkylenedioxy group     together with the phenyl group they are attached to, each of said     substituents being optionally substituted by one or more further     substituents selected from halo, cyano, alkyl, haloalkyl, hydroxyl,     alkoxy, haloalkoxy, more preferably R⁸, R^(8′), R⁹, R^(9′) and R¹⁰     are independently selected from H, halo preferably bromo, fluoro or     chloro, cyano, C₁-C₄ alkyl preferably methyl, aryl preferably     phenyl, alkoxy preferably methoxy, still more preferably R⁸, R^(8′),     R⁹, R^(9′) and R¹⁰ are independently selected from H, halo     preferably bromo, fluoro or chloro, alkyl preferably methyl, still     more preferably R⁸ is Br, Cl or F, preferably Cl and R^(8′), R⁹,     R^(9′) and R¹⁰ are independently selected from H or F, or R⁹ is Cl     or F and R⁸, R^(8′), R^(9′) and R¹⁰ are H, or R⁹ and R^(9′) are F     and R⁸, R^(8′) and R¹⁰ are H, or R¹⁰ is Cl or F and R⁸, R^(8′), R⁹     and R^(9′) are H, even more preferably R⁸ is Br, Cl or F and R^(8′),     R⁹, R^(9′) and R¹⁰ are H, or R⁸ and R⁹ are F and R^(8′), R^(9′) and     R¹⁰ are H, or R⁸ and R¹⁰ are F and R^(8′), R⁹ and R^(9′) are H;

R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably —OCF₃ or —OCHF₂, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkyloxycarbonyl, aminoalkyl alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocyclylcarbonylamino arylcarbonylamino, heteroarylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, heterocyclylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, haloalkylsulfonylamino, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form together a cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably trifluoromethoxy, 1,1,1-trifluoroethyloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, cycloalkylsulfonylamino, haloalkylsulfonylamino and oxo, preferably R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from H, halo preferably chloro and fluoro more preferably chloro, cyano, nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl, cycloalkylalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy preferably —OCF₃ or —OCHF₂, alkoxyalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, alkylsulfamoyl, arylsulfamoyl, heteroarylsulfamoyl, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form together an aryl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanomethyl, cycloalkyl, heterocyclyl, aryl optionally substituted by one a chloro or methyl group, heteroaryl, heteroalkyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy preferably 1,1,1-trifluoroethyloxy, alkoxyalkyl, cycloalkyloxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyloxy preferably carbamoylmethyloxy carbamoylamino, alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl preferably phenylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino and oxo, more preferably R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl, haloalkyl preferably CF₃ or CHF₂, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy preferably OCF₃ or OCHF₂, alkoxyalkoxy, aryloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylcarbonyl, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form an alkylenedioxy group or a haloalkylenedioxy group together with the phenyl group they are attached to, or one or more of R¹¹ and R¹², or R¹² and R¹⁶, or R¹⁶ and R^(12′), or R^(12′) and R^(11′) form together an aryl, or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, ethyl, propyl, isopropyl, tert-butyl, cyanomethyl, cycloalkyl, heterocyclyl, alkoxy preferably methoxy, ethoxy, isopropoxy, alkoxyalkyl, alkoxyalkoxy, cycloalkylalkyloxy, aryloxy, aralkyloxy optionally substituted by one fluoro, amino, alkylamino, alkylcarbonylamino, carbamoyl, hydroxycarbamimidoyl, alkylsulfonyl, alkylsulfonylamino, still more preferably R¹¹, R^(11′), R¹², R^(12′) and R¹⁶ are independently selected from H, halo preferably chloro and fluoro, cyano, nitro, alkyl preferably methyl, ethyl, isopropyl or isobutyl, haloalkyl preferably CF₃ or CHF₂, cycloalkyl preferably cyclohexyl, heterocyclyl preferably pyrrolidin-1-yl, 4-methylpiperidin-1-yl, aryl preferably phenyl, heteroaryl preferably thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, aralkyl preferably benzyl, alkoxy preferably methoxy, ethoxy or isopropyloxy, cycloalkylalkyloxy, arylalkyloxy preferably benzyloxy, phenethyloxy or 3,3-diphenylpropan-1-oxy, heteroarylalkyloxy preferably pyridylmethyloxy or pyridylethyloxy, aryloxyalkyl preferably phenoxymethyl, heteroaryloxyalkyl preferably pyridyloxymethyl, or two substituents form an haloalkylenedioxy group each of said substituents being optionally substituted by one or more further substituents selected from halo preferably chloro or fluoro, cyano, alkyl preferably methyl, haloalkyl preferably trifluoromethyl, alkoxy preferably methoxy, isopropyloxy, isobutyloxy, alkoxyalkyl preferably methoxymethyl, alkoxyalkoxy preferably 2-methoxyethoxy, cycloalkyl alkyloxy preferably cyclopropylmethyloxy, aryloxy preferably phenoxy, aralkyloxy optionally substituted by one fluoro, preferably benzyloxy, 4-fluorobenzyloxy, amino, alkylcarbonylamino preferably acetylamino, alkylsulfonyl preferably methylsulfonyl, alkylsulfonylamino preferably methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino.

Preferred compounds of formula Ie-1g are those of formula Ie-1h1:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R⁸, R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Ie-1g; -   R¹² is as defined above in respect to formula Ie-1g, preferably R¹²     is H, fluoro, chloro, methyl, CF₃, nitro, cyano, methoxy or     cyclopropylmethyloxy; -   R¹³, R^(13′), R¹⁴, R^(14′) and R¹⁵ are as defined above in respect     to formula Ie-1g, preferably R^(13′), R¹⁴, R^(14′) and R¹⁵ are H and     R¹³ is chloro, cyano, hydroxyl, methyl, trifluoromethyl,     cyanomethyl, methoxy, isopropoxy, isobutyloxy, OCF₃,     cyclopropylmethyloxy, phenoxy, cyclopropylmethyloxy, benzyloxy,     (4-fluorobenzyl)oxy, methoxymethyl, 2-methoxyethoxy,     carbamoylmethyloxy, or R¹³, R^(13′), R^(14′) and R¹⁵ are H and R¹⁴     is chloro, methylsulfonylamino, or R¹³, R^(13′), R¹⁴ and R^(14′) are     H and R¹⁵ is chloro, methylsulfonylamino, R¹³R¹⁴ and R^(14′) are H     and R¹³ and R¹⁵ are a) independently selected from chloro or     methoxy, or b) both F, or c) R¹³ is F and R¹⁵ is methoxy, or d) R¹³     is methoxy and R¹⁵ is F, or e) R¹³ is methoxy and R¹⁵ is     acetylamino, or f) R¹³ is methoxy and R¹⁵ is amino, or g) R¹³ is     cyano and R¹⁵ is methoxy, or h) R¹³ is chloro and R¹⁵ is cyano,     or i) R¹³ is cyano and R¹⁵ is trifluoromethyl, or f) R¹³ is methoxy     and R¹⁵ is (N-methyl-N-methylsulfonyl)amino, or R¹⁴, R^(14′) and R¹⁵     are H and both R¹³ and R^(13′) are methoxy, or R¹³, R^(13′) and R¹⁵     are H and both R¹⁴ and R^(14′) are fluoro, methoxy, or R¹³, R^(13′)     and R^(14′) are H and a) R¹⁴ forms together with R¹⁵ a phenyl moiety     fused to the phenyl ring they are attached to, or b) both R¹⁴ and     R¹⁵ are methoxy, or R^(13′), R^(14′) and R¹⁵ are H and R¹³ and R¹⁴     are a) both methoxy, or b) R¹³ is methyl and R¹⁴ is     methylsulfonylamino, or c) R¹³ is methoxy and R¹⁴ is cyano, or d) is     methyl and R¹⁴ is amino, or R^(13′), R¹⁴ and R¹⁵ are H and R¹³ and     R^(14′) are a) both methoxy, or b) R¹³ is methoxy and R^(14′) is     cyano, or c) R¹³ is methyl and R^(14′) is cyano, or R¹³ and R¹⁴ are     H and R^(13′), R^(14′) and R¹⁵ are methoxy, or R¹⁴ and R¹⁵ are H and     R¹³, R^(13′) and R^(14′) are methoxy, or R¹³ and R¹⁴ are methoxy and     R^(13′) and R¹⁵ are H and R^(14′) is cyano, or R¹⁴ and R¹⁵ are     methoxy and R¹³ and R^(14′) are H and R^(13′) is cyano, or R¹³ and     R^(13′) are H and R¹⁴, R^(14′) and R¹⁵ are methoxy, more preferably     R^(13′), R¹⁴, R^(14′) and R¹⁵ are H and R¹³ is chloro, cyano,     trifluoromethyl, methoxy, isopropoxy, cyclopropylmethyloxy, or R¹³,     R^(13′), R^(14′) and R¹⁵ are H and R¹⁴ is chloro, or R¹³, R^(13′),     R¹⁴ and R^(14′) are H and R¹⁵ is chloro, methylsulfonylamino, or     R^(13′), R¹⁴ and R^(14′) are H and R¹³ and R¹⁵ are a) independently     selected from chloro or methoxy, or b) both F, or c) R¹³ is F and     R¹⁵ is methoxy, or d) R¹³ is methoxy and R¹⁵ is F, or e) R¹³ is     methoxy and R¹⁵ is acetylamino, R¹³ is methoxy and R¹⁵ is amino,     or g) R¹³ is cyano and R¹⁵ is methoxy, or h) R¹³ is chloro and R¹⁵     is cyano, or i) R¹³ is cyano and R¹⁵ is trifluoromethyl, or j) R¹³     is methoxy and R¹⁵ is (N-methyl-N-methylsulfonyl)amino, or R¹⁴,     R^(14′) and R¹⁵ are H and both R¹³ and R^(13′) are methoxy, or R¹³,     R^(13′) and R^(14′) are H and a) R¹⁴ forms together with R¹⁵ a     phenyl moiety fused to the phenyl ring they are attached to, or b)     both R¹⁴ and R¹⁵ are methoxy, or R^(13′), R^(14′) and R¹⁵ are H and     R¹³ and R¹⁴ are a) both methoxy, or b) R¹³ is methyl and R¹⁴ is     methylsulfonylamino, or c) R¹³ is methoxy and R¹⁴ is cyano, or d)     R¹³ is methyl and R¹⁴ is amino, or R^(13′), R¹⁴ and R¹⁵ are H and     R¹³ and R^(14′) are a) both methoxy, or b) R¹³ is methoxy and     R^(14′) is cyano, or c) R¹³ is methyl and R^(14′) is cyano, or R¹³     and R¹⁴ are H and R^(13′), R^(14′) and R¹⁵ are methoxy, or R¹⁴ and     R¹⁵ are H and R¹³, R^(13′) and R^(14′) are methoxy, or R¹³ and R¹⁴     are methoxy and R^(13′) and R¹⁵ are H and R^(14′) is cyano, or R¹⁴     and R¹⁵ are methoxy and R¹³ and R^(14′) are H and R^(13′) is cyano,     or R¹³ and R^(13′) are H and R¹⁴, R^(14′) and R¹⁵ are methoxy.

Other preferred compounds of formula Ie-1g are those of formula Ie-1h′:

and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein

-   R is as defined above in respect to formula I; -   R⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are as defined above in respect to     formula Ie-1g; -   R¹² is as defined above in respect to formula Ie-1g, preferably R¹²     is H, fluoro, chloro, methyl, CF₃, or methoxy more preferably R¹² is     H or methoxy; -   R¹⁶ is selected from the group of heteroaryl moieties consisting of:

wherein the arrow marks the attachment point to the phenyl ring;

-   R¹⁷, R^(17′), R¹⁸, R^(18′) and R¹⁹ are independently selected from     H, halo preferably chloro and fluoro, cyano, alkyl preferably     methyl, ethyl, propyl, isopropyl, tert-butyl, haloalkyl preferably     CF₃ or CHF₂, hydroxyl, hydroxyalkyl, alkoxy preferably methoxy,     ethoxy, isopropyloxy, haloalkoxy preferably OCF₃, OCHF₂, or     1,1,1-trifluoroethyloxy, alkoxyalkoxy, cycloalkyloxy, alkoxyalkyl     preferably methoxymethyl, cycloalkylalkyloxy preferably     cyclopropylmethyloxy, aralkyloxy preferably benzyloxy,     haloalkoxyalkyl, amino, alkylamino, alkylcarbonylamino,     haloalkylcarbonylamino, alkylcarbonylaminoalkyl, carbamoyl,     hydroxycarbamoyl, alkylcarbamoyl, carbamoylamino,     alkylcarbamoylamino, carbamimidoyl, hydroxycarbamimidoyl,     alkylsulfonyl preferably methylsulfonyl, haloalkylsulfonyl,     sulfamoyl, alkylsulfamoyl, alkylsulfonylamino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino,     haloalkylsulfonylamino, preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are     independently selected from H, halo preferably chloro and fluoro,     cyano, alkyl preferably methyl, ethyl, propyl, isopropyl,     tert-butyl, haloalkyl preferably CF₃, alkoxy preferably methoxy,     ethoxy, isopropyloxy, haloalkoxy preferably OCF₃, OCHF₂, or     1,1,1-trifluoroethyloxy, alkoxyalkyl preferably methoxymethyl,     aralkyloxy preferably benzyloxy, amino, alkylcarbonylamino,     carbamoyl, carbamimidoyl, hydroxycarbamimidoyl, alkylsulfonyl     preferably methylsulfonyl, alkylsulfonylamino preferably     methylsulfonylamino, (N-methyl-N-methylsulfonyl)amino, more     preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected     from H, halo preferably chloro, alkoxy preferably methoxy, even more     preferably R¹⁷, R^(17′), R^(18′) and R¹⁹ are independently selected     from H, halo preferably chloro, alkoxy preferably methoxy;

Preferred compounds of formula Ie-1h′ are those wherein R¹⁶ is selected from 2-2-methoxypyrimidin-4-yl, 2,4-dibenzyloxypyrimidin-5-yl, 2,4-dimethoxypyrimidin-5-yl, 3,6-dimethoxypyridazin-5-yl, 2-methoxypyrimidin-5-yl, 2-methoxypyrimidin-3-yl.

Particularly preferred compounds of the invention are those listed in Table 1 hereafter:

TABLE 1 Com- pound no Compound name (M + H)⁺ 1 (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 2 (2S,5R)-5-(2-chlorophenyl)-1-(2′-methyl-[1,1′- 420.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 3 (2S,5R)-1-(3-((4-chlorobenzyl)oxy)-5- 501.4 methoxybenzoyl)-5-(2-chlorophenyl)pyrrolidine- 2-carboxylic acid 4 (2S,5R)-5-(2-chlorophenyl)-1-(2′-fluoro-[1,1′- 424.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 5 (2S,5R)-5-(2-chlorophenyl)-1-(4′-methyl-[1,1′- 420.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 6 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-5- 481.0 phenethoxybenzoyl)pyrrolidine-2-carboxylic acid 8 (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5-(2- 406.9 chlorophenyl)pyrrolidine-2-carboxylic acid 9 (2S,5R)-5-(2-chlorophenyl)-1-(3-(3,3- 571.1 diphenylpropoxy)-5-methoxybenzoyl)pyrrolidine- 2-carboxylic acid 10 (2S,5R)-5-(2-chlorophenyl)-1-(3′-fluoro-[1,1′- 424.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 11 (2S,5R)-5-(2-chlorophenyl)-1-(3′-methyl-[1,1′- 420.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 12 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-5-((4- 545.0 (methylsulfonyl)benzyl)oxy)benzoyl)pyrrolidine- 2-carboxylic acid 13 (2S,5R)-5-(2-chlorophenyl)-1-(3′-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 14 (2S,5R)-5-(2-chlorophenyl)-1-(3,5- 390.8 dimethoxybenzoyl)pyrrolidine-2-carboxylic acid 15 (2S,5R)-5-(2-chlorophenyl)-1-(4- 436.9 (phenoxymethyl)benzoyl)pyrrolidine-2-carboxylic acid 16 (2S,5R)-5-(2-chlorophenyl)-1-(4-((2- 454.9 fluorobenzyl)oxy)benzoyl)pyrrolidine-2- carboxylic acid 17 (2S,5R)-1-(3-chloro-5-methoxybenzoyl)-5-(2- 395.2 chlorophenyl)pyrrolidine-2-carboxylic acid 18 (2S,5R)-5-(2-chlorophenyl)-1-(4′-fluoro-[1,1′- 424.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 19 (2S,5R)-5-(2-chlorophenyl)-1-(4- 450.9 phenethoxybenzoyl)pyrrolidine-2-carboxylic acid 20 (2S,5R)-5-(2-chlorophenyl)-1-(chroman-3- 386.8 carbonyl)pyrrolidine-2-carboxylic acid 21 (2S,5R)-5-(2-chlorophenyl)-1-(3,5- 418.9 diethoxybenzoyl)pyrrolidine-2-carboxylic acid 23 (2S,5R)-5-(2-chlorophenyl)-1-(3- 450.9 phenethoxybenzoyl)pyrrolidine-2-carboxylic acid 24 (2S)-1-([1,1′-biphenyl]-4-carbonyl)-4-benzyl-5- 462.6 phenylpyrrolidine-2-carboxylic acid 25 (2S,5R)-5-(2-chlorophenyl)-1-(1,2,3,4- 384.9 tetrahydronaphthalene-2-carbonyl)pyrrolidine-2- carboxylic acid 26 (2S,5R)-5-(2-chlorophenyl)-1-(4- 386.9 isobutylbenzoyl)pyrrolidine-2-carboxylic acid 27 (2S,5R)-5-(2-chlorophenyl)-1-(2,2- 410.8 difluorobenzo[d][1,3]dioxole-6- carbonyl)pyrrolidine-2-carboxylic acid 28 (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5- 372.4 phenylpyrrolidine-2-carboxylic acid 29 (2S,5R)-5-(2-chlorophenyl)-1-(3-fluoro-5- 378.8 methoxybenzoyl)pyrrolidine-2-carboxylic acid 30 (2S,5R)-5-(2-chlorophenyl)-1-(6- 407.9 phenylnicotinoyl)pyrrolidine-2-carboxylic acid 31 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-5-(2- 434.9 methoxyethoxy)benzoyl)pyrrolidine-2-carboxylic acid 32 (2S,5R)-5-(2-chlorophenyl)-1-(3′-methoxy-[1,1′- 436.9 biphenyl]-3-carbonyl)pyrrolidine-2-carboxylic acid 33 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-5- 428.8 (trifluoromethyl)benzoyl)pyrrolidine-2-carboxylic acid 34 (2S,5R)-5-(2-chlorophenyl)-1-(1-(4- 503.0 methoxyphenyl)-5-pheny 1-1H-pyrazole-3- carbonyl)pyrrolidine-2-carboxylic acid 35 (2S,5R)-5-(2-chlorophenyl)-1-(4- 388.9 isopropoxybenzoyl)pyrrolidine-2-carboxylic acid 36 (2S,5R)-5-(2-chlorophenyl)-1-(3-((3,5- 485.9 dimethylisoxazol-4-yl)methoxy)-5- methoxybenzoyl)pyrrolidine-2-carboxylic acid 37 (2S,5R)-5-(2-chlorophenyl)-1-(2,3-dihydro-1H- 370.8 indene-2-carbonyl)pyrrolidine-2-carboxylic acid 38 (2S,5R)-5-(2-chlorophenyl)-1-(3-methyl-5- 428.8 (trifluoromethoxy)benzoyl)pyrrolidine-2- carboxylic acid 39 (2S,5R)-1-(3-(benzyloxy)benzoyl)-5-(2- 436.9 chlorophenyl)pyrrolidine-2-carboxylic acid 40 (2S,5R)-5-(2-chlorophenyl)-1-(3- 360.8 methoxybenzoyl)pyrrolidine-2-carboxylic acid 41 (2S,5R)-5-(2-chlorophenyl)-1-(2- 408.9 phenylpyrimidine-5-carbonyl)pyrrolidine-2- carboxylic acid 42 (2S,5R)-5-(2-chlorophenyl)-1-(4- 414.8 (trifluoromethoxy)benzoyl)pyrrolidine-2- carboxylic acid 43 (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-cyclopropyl- 438.9 1,2,4-oxadiazol-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 44 4-((2S,5R)-2-carboxy-5-(2- 438.8 chlorophenyl)pyrrolidine-1-carbonyl)-2,6- dimethoxypyrimidin-1-ium formate 45 (2S,5R)-5-(2-chlorophenyl)-1-(4- 372.9 phenylbutanoyl)pyrrolidine-2-carboxylic acid 46 (2S,5R)-5-(2-chlorophenyl)-1-(3-methyl-5- 412.8 (trifluoromethyl)benzoyl)pyrrolidine-2-carboxylic acid 47 (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5-(3- 407.9 chloropyridin-2-yl)pyrrolidine-2-carboxylic acid 48 (2S,5R)-5-(2-chlorophenyl)-1-(3-hydroxy-5- 414.8 (trifluoromethyl)benzoyl)pyrrolidine-2-carboxylic acid 49 (2S,5S)-5-(2-chlorophenyl)-1-(3- 360.8 methoxybenzoyl)pyrrolidine-2-carboxylic acid 50 (2S,5R)-1-(3,5-dimethoxybenzoyl)-5- 356.4 phenylpyrrolidine-2-carboxylic acid 51 (S)-5-([1,1′-biphenyl]-3-yl)-1-(3- 402.5 methoxybenzoyl)pyrrolidine-2-carboxylic acid 52 (2S,5R)-5-(2-chlorophenyl)-1-(3- 358.8 phenylpropanoyl)pyrrolidine-2-carboxylic acid 53 (2S,5S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 54 (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5-(pyridin- 373.4 2-yl)pyrrolidine-2-carboxylic acid 55 (2S,5R)-5-(2-chlorophenyl)-1-(5- 407.9 phenylpicolinoyl)pyrrolidine-2-carboxylic acid 57 (2S,5R)-5-(2-fluorophenyl)-1-(3- 344.3 methoxybenzoyl)pyrrolidine-2-carboxylic acid 58 (2S,5R)-1-(2-([1,1′-biphenyl]-4-yl)acetyl)-5-(2- 420.9 chlorophenyl)pyrrolidine-2-carboxylic acid 59 (2R,5S)-1-([1,1′-biphenyl]-4-carbonyl)-5- 372.4 phenylpyrrolidine-2-carboxylic acid 60 (2S,5R)-5-phenyl-1-(2-phenylacetyl)pyrrolidine-2- 310.4 carboxylic acid 61 (2R,5S)-5-phenyl-1-(2-phenylacetyl)pyrrolidine-2- 310.4 carboxylic acid 62 (2S,5R)-1-(3-methoxybenzoyl)-5-(2- 356.4 methoxyphenyl)pyrrolidine-2-carboxylic acid 63 (2R,5S)-5-(2-chlorophenyl)-1-(3- 360.8 methoxybenzoyl)pyrrolidine-2-carboxylic acid 64 (2R,5R)-5-(2-chlorophenyl)-1-(3- 360.8 methoxybenzoyl)pyrrolidine-2-carboxylic acid 65 (2S)-5-(4-chlorophenyl)-1-(3- 360.8 methoxybenzoyl)pyrrolidine-2-carboxylic acid 66 (2S)-5-([1,1′-biphenyl]-4-yl)-1-(3- 402.5 methoxybenzoyl)pyrrolidine-2-carboxylic acid 67 (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3- 374.8 methoxybenzoyl)pyrrolidine-2-carboxylate 68 (2S)-5-(2-chlorobenzyl)-1-(3- 374.8 methoxybenzoyl)pyrrolidine-2-carboxylic acid 69 (2S)-5-cyclohexyl-1-(3- 332.4 methoxybenzoyl)pyrrolidine-2-carboxylic acid 70 (2S,5R)-5-(2-chlorophenyl)-1-(2-(3- 374.8 methoxyphenyl)acetyl)pyrrolidine-2-carboxylic acid 71 (2S,5S)-5-(2-chlorophenyl)-1-(3,5- 390.8 dimethoxybenzoyl)pyrrolidine-2-carboxylic acid 72 (2S,5R)-5-([1,1′-biphenyl]-2-yl)-1-(3- 402.5 methoxybenzoyl)pyrrolidine-2-carboxylic acid 74 2-((2S,5R)-5-(2-chlorophenyl)-1-(3- 374.8 methoxybenzoyl)pyrrolidin-2-yl)acetic acid 75 (2S,5R)-5-(2-chlorophenyl)-1-(6- 408.9 phenylpyrimidine-4-carbonyl)pyrrolidine-2- carboxylic acid 76 (2S,5R)-5-(2-chlorophenyl)-1-(6-(2- 425.9 fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid 77 (2S,5R)-5-(2-chlorophenyl)-1-(6-(2- 442.3 chlorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid 78 (2S,5R)-5-(2-chlorophenyl)-1-(6-(2- 437.9 methoxyphenyl)nicotinoyl)pyrrolidine-2- carboxylic acid 79 (2S,5R)-5-(2-chlorophenyl)-1-(6-(3- 425.9 fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid 80 (2S,5R)-5-(2-chlorophenyl)-1-(6-(3- 437.9 methoxyphenyl)nicotinoyl)pyrrolidine-2- carboxylic acid 81 (2S,5R)-5-(2-chlorophenyl)-1-(6-(4- 437.9 methoxyphenyl)nicotinoyl)pyrrolidine-2- carboxylic acid 82 (2S,5R)-5-(2-chlorophenyl)-1-(6-(4- 425.9 fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid 83 (2S,5R)-5-(2-chlorophenyl)-1-(2-(2- 443.3 chlorophenyl)pyrimidine-5-carbonyl)pyrrolidine- 2-carboxylic acid 84 (2S,5R)-5-(2-chlorophenyl)-1-(2-methyl-6- 421.9 phenylnicotinoyl)pyrrolidine-2-carboxylic acid 85 (2S,5R)-1-(4-chloro-2-(pyridin-3-yl)pyrimidine-5- 444.3 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 86 (2S,5R)-1-(4-chloro-2-(pyridin-2-yl)pyrimidine-5- 444.3 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 87 (2S,5R)-1-(4-chloro-2-(pyridin-4-yl)pyrimidine-5- 444.3 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 88 (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-2- 407.9 yl)benzoyl)pyrrolidine-2-carboxylic acid 89 (2S,5R)-1-(4-((4-chlorophenoxy)methyl)benzoyl)- 471.3 5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid 90 (2S,5R)-5-(2-chlorophenyl)-1-(4-((4- 454.9 fluorophenoxy)methyl)benzoyl)pyrrolidine-2- carboxylic acid 91 (2S,5R)-5-(2-chlorophenyl)-1-(4-((4- 466.9 methoxyphenoxy)methyl)benzoyl)pyrrolidine-2- carboxylic acid 92 (2S,5R)-1-(4-((2-chlorophenoxy)methyl)benzoyl)- 471.3 5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid 93 (2S,5R)-5-(2-chlorophenyl)-1-(4-((2- 466.9 methoxyphenoxy)methyl)benzoyl)pyrrolidine-2- carboxylic acid 94 (2S,5R)-5-(2-chlorophenyl)-1-(4-((3- 466.9 methoxyphenoxy)methyl)benzoyl)pyrrolidine-2- carboxylic acid 95 (2S,5R)-1-(4-((3-chlorophenoxy)methyl)benzoyl)- 471.3 5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid 96 (2S,5R)-5-(2-chlorophenyl)-1-(4-((p- 450.9 tolyloxy)methyl)benzoyl)pyrrolidine-2-carboxylic acid 97 (2S,5R)-5-(2-chlorophenyl)-1-(4-((3- 466.9 methoxybenzyl)oxy)benzoyl)pyrrolidine-2- carboxylic acid 98 (2S,5R)-1-(4-((3-chlorobenzyl)oxy)benzoyl)-5-(2- 471.3 chlorophenyl)pyrrolidine-2-carboxylic acid 99 (2S,5R)-5-(2-chlorophenyl)-1-(4-((3,5- 455.9 dimethylisoxazol-4- yl)methoxy)benzoyl)pyrrolidine-2-carboxylic acid 100 (2S,5R)-5-(2-chlorophenyl)-1-(4-((3,5-dimethyl- 454.9 1H-pyrazol-1-yl)methoxy)benzoyl)pyrrolidine-2- carboxylic acid 101 (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-2- 437.9 ylmethoxy)benzoyl)pyrrolidine-2-carboxylic acid 102 (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-4- 437.9 ylmethoxy)benzoyl)pyrrolidine-2-carboxylic acid 103 (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-3- 437.9 ylmethoxy)benzoyl)pyrrolidine-2-carboxylic acid 104 (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-methyl-1H- 410.9 pyrazol-1-yl)benzoyl)pyrrolidine-2-carboxylic acid 105 (2S,5R)-5-(2-chlorophenyl)-1-(4-(isoxazol-5- 397.8 yl)benzoyl)pyrrolidine-2-carboxylic acid 106 (2S,5R)-1-(4-(4H-1,2,4-triazol-4-yl)benzoyl)-5-(2- 397.8 chlorophenyl)pyrrolidine-2-carboxylic acid 107 (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-(p-tolyl)-1H- 488.0 1,2,3-triazol-1-yl)benzoyl)pyrrolidine-2- carboxylic acid 108 (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-oxo-3-phenyl- 488.9 4,5-dihydro-1H-pyrazol-1-yl)benzoyl)pyrrolidine- 2-carboxylic acid 109 (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-methyl-3- 478.9 (trifluoromethyl)-1H-pyrazol-1- yl)benzoyl)pyrrolidine-2-carboxylic acid 110 (2S,5R)-1-(4-(1H-pyrazol-1-yl)benzoyl)-5-(2- 396.8 chlorophenyl)pyrrolidine-2-carboxylic acid 111 (2S,5R)-5-(2-chlorophenyl)-1-(4-(oxazol-5- 397.8 yl)benzoyl)pyrrolidine-2-carboxylic acid 112 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3,5-dimethyl- 424.9 1H-pyrazol-1-yl)benzoyl)pyrrolidine-2-carboxylic acid 113 (2S,5R)-5-(2-chlorophenyl)-1-(2′,5′-dichloro-[1,1′- 475.8 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 114 (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyrimidin-5- 408.9 yl)benzoyl)pyrrolidine-2-carboxylic acid 115 (2S,5R)-5-(2-chlorophenyl)-1-(4-(furan-3- 396.8 yl)benzoyl)pyrrolidine-2-carboxylic acid 116 (2S,5R)-5-(2-chlorophenyl)-1-(4-(6- 437.9 methoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 117 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3-fluoropyridin- 425.9 4-yl)benzoyl)pyrrolidine-2-carboxylic acid 118 (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-3- 407.9 yl)benzoyl)pyrrolidine-2-carboxylic acid 119 (2S,5R)-5-(2-chlorophenyl)-1-(4-(6- 450.9 (dimethylamino)pyridin-3-yl)benzoyl)pyrrolidine- 2-carboxylic acid 120 (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-4- 407.9 yl)benzoyl)pyrrolidine-2-carboxylic acid 121 (2S,5R)-5-(2-chlorophenyl)-1-(4-(6- 421.9 methylpyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 122 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- 437.9 methoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 123 (2S,5R)-5-(2-chlorophenyl)-1-(4′-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 124 (2S,5R)-5-(2-chlorophenyl)-1-(4′-cyano-[1,1′- 431.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 125 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4- 437.9 methoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 126 (2S,5R)-1-(4′-chloro-[1,1′-biphenyl]-4-carbonyl)- 441.3 5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid 127 (2S,5R)-1-(3′-chloro-[1,1′-biphenyl]-4-carbonyl)- 441.3 5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid 128 (2S,5R)-1-(2′-chloro-[1,1′-biphenyl]-4-carbonyl)- 441.3 5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid 129 (2S,5R)-5-(2-chlorophenyl)-1-(4′- 500.0 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 130 (2S,5R)-5-(2-chlorophenyl)-1-(3′- 500.0 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 131 (2S,5R)-5-(2-chlorophenyl)-1-(2′- 500.0 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 132 (2S,5R)-5-(2-chlorophenyl)-1-(4-(naphthalen-2- 456.9 yl)benzoyl)pyrrolidine-2-carboxylic acid 133 (2S,5R)-5-(2-chlorophenyl)-1-(3′,5′-difluoro-[1,1′- 442.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 134 (2S,5R)-5-(2-chlorophenyl)-1-(2′-hydroxy-[1,1′- 422.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 135 (2S,5R)-5-(2-chlorophenyl)-1-(2′- 490.9 (trifluoromethoxy)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 136 (2S,5R)-1-(2′-(benzyloxy)-[1,1′-biphenyl]-4- 513.0 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 137 (2S,5R)-5-(2-chlorophenyl)-1-(2′-phenoxy-[1,1′- 499.0 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 138 (2S,5R)-5-(2-chlorophenyl)-1-(2′-isopropoxy- 465.0 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 139 (2S,5R)-5-(2-chlorophenyl)-1-(2′-isobutoxy-[1,1′- 479.0 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 140 (2S,5R)-5-(2-chlorophenyl)-1-(2′- 477.0 (cyclopropylmethoxy)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 141 (2S,5R)-5-(2-chlorophenyl)-1-(2′-((4- 531.0 fluorobenzyl)oxy)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 142 (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-chloropyridin- 442.3 3-yl)benzoyl)pyrrolidine-2-carboxylic acid 143 (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-fluoropyridin- 425.9 3-yl)benzoyl)pyrrolidine-2-carboxylic acid 144 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-chloropyridin- 442.3 4-yl)benzoyl)pyrrolidine-2-carboxylic acid 145 (2S,5R)-1-(4-(2-chloro-3-fluoropyridin-4- 460.3 yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 146 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-chloropyridin- 442.3 3-yl)benzoyl)pyrrolidine-2-carboxylic acid 147 (2S,5R)-1-(4-(6-(benzyloxy)pyridin-3-yl)benzoyl)- 514.0 5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid 148 (2S,5R)-1-(4-(1H-pyrazol-4-yl)benzoyl)-5-(2- 396.8 chlorophenyl)pyrrolidine-2-carboxylic acid 149 (2S,5R)-5-(2-chlorophenyl)-1-(4-(thiophen-3- 412.9 yl)benzoyl)pyrrolidine-2-carboxylic acid 150 (2S,5R)-5-(2-chlorophenyl)-1-(4- 412.9 cyclohexylbenzoyl)pyrrolidine-2-carboxylic acid 151 (2S,5R)-5-(2-chlorophenyl)-1-(4′- 485.0 (methylsulfonyl)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 152 (2S,5R)-5-(2-chlorophenyl)-1-(9-oxo-9H-fluorene- 432.9 2-carbonyl)pyrrolidine-2-carboxylic acid 153 (2S,5R)-5-(2-chlorophenyl)-1-(2′- 485.0 (methylsulfonyl)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 154 (2S,5R)-5-(2-chlorophenyl)-1-(4-(tetrahydro-2H- 414.9 pyran-4-yl)benzoyl)pyrrolidine-2-carboxylic acid 155 (2S,5R)-5-(2-chlorophenyl)-1-(9-methyl-9H- 433.9 carbazole-2-carbonyl)pyrrolidine-2-carboxylic acid 156 (2S,5R)-5-(2-chlorophenyl)-1-(4- 422.9 phenoxybenzoyl)pyrrolidine-2-carboxylic acid 157 (2S,5R)-1-(4-benzylbenzoyl)-5-(2- 420.9 chlorophenyl)pyrrolidine-2-carboxylic acid 158 (2S,5R)-1-(4-benzoylbenzoyl)-5-(2- 434.9 chlorophenyl)pyrrolidine-2-carboxylic acid 159 (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyrimidin-2- 408.9 yl)benzoyl)pyrrolidine-2-carboxylic acid 160 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6- 468.9 dimethoxypyrimidin-2-yl)benzoyl)pyrrolidine-2- carboxylic acid 161 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4- 468.9 dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 162 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- 438.9 methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 163 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- 451.9 (dimethylamino)pyrimidin-5- yl)benzoyl)pyrrolidine-2-carboxylic acid 164 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- 494.0 morpholinopyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 165 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-(piperidin-1- 492.0 yl)pyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 168 (2S,5R)-5-(2-chlorophenyl)-1- 336.8 (cyclohexanecarbonyl)pyrrolidine-2-carboxylic acid 169 (2S,5R)-5-(2-chlorophenyl)-1-(4- 324.8 methylpentanoyl)pyrrolidine-2-carboxylic acid 172 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4- 472.9 methylpiperidin-1-yl)-3-nitrobenzoyl)pyrrolidine- 2-carboxylic acid 173 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-oxopiperidin- 427.9 1-yl)benzoyl)pyrrolidine-2-carboxylic acid 174 (2S,5R)-5-(2-chlorophenyl)-1-(3-methyl-4- 429.9 morpholinobenzoyl)pyrrolidine-2-carboxylic acid 175 (2S,5R)-5-(2-chlorophenyl)-1-(4-(piperidin-1- 413.9 yl)benzoyl)pyrrolidine-2-carboxylic acid 176 (2S,5R)-5-(2-chlorophenyl)-1-(4- 415.9 morpholinobenzoyl)pyrrolidine-2-carboxylic acid 177 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2- 438.9 cyanophenyl)piperidine-4-carbonyl)pyrrolidine-2- carboxylic acid 178 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4- 447.4 chlorophenyl)cyclohexanecarbonyl)pyrrolidine-2- carboxylic acid 179 (2S,5R)-5-(2-chlorophenyl)-1-(4- 412.9 phenylcyclohexanecarbonyl)pyrrolidine-2- carboxylic acid 183 ((2R,5S)-2-(2-chlorophenyl)-5-(1H-tetrazol-5- 460.9 yl)pyrrolidin-1-yl)(2′-methoxy-[1,1′-biphenyl]-4- yl)methanone 184 (2R,5S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 189 (2S,5R)-5-(2-chlorophenyl)-1-(6-(2- 425.9 fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid 191 (2S,5R)-5-(2-chlorophenyl)-1-(5-methoxy-6- 437.9 phenylnicotinoyl)pyrrolidine-2-carboxylic acid 192 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- 452.9 methoxyphenoxy)benzoyl)pyrrolidine-2-carboxylic acid 193 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3- 437.9 methoxypyridin-4-yl)benzoyl)pyrrolidine-2- carboxylic acid 194 (2S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′- 465.0 biphenyl]-4-carbonyl)-4,4-dimethylpyrrolidine-2- carboxylic acid 195 (2S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′- 450.9 biphenyl]-4-carbonyl)-4-methylpyrrolidine-2- carboxylic acid 196 (2S,5R)-5-(2-chlorophenyl)-1-(2-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 197 (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-[1,1′- 431.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 198 (2S,5R)-5-(2-chlorophenyl)-1-(2′,6′-dimethoxy- 466.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 199 (2S,5R)-5-(2-chlorophenyl)-1-(2′,4′-dichloro-[1,1′- 475.8 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 200 (2S,5R)-5-(2-chlorophenyl)-1-(2′-(trifluoromethyl)- 474.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 201 (2S,5R)-5-(2-chlorophenyl)-1-(2,2′-dimethoxy- 466.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 202 (2S,5R)-1-(4′-chloro-2′-methoxy-[1,1′-biphenyl]-4- 471.3 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 203 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4- 438.9 methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 204 (2S,5R)-5-(2-chlorophenyl)-1-(2′,4′-dimethoxy- 466.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 205 (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5-(pyridin- 373.4 3-yl)pyrrolidine-2-carboxylic acid 206 (2R,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 207 (2S,5R)-5-(2-chlorophenyl)-1-(1-phenyl-1H- 446.9 benzo[d]imidazole-5-carbonyl)pyrrolidine-2- carboxylic acid 208 (2S,5R)-methyl 5-(2-chlorophenyl)-1-(2′-methoxy- 450.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylate 211 (2S,4S,5R)-5-(2-chlorophenyl)-4-(hydroxymethyl)- 466.9 1-(2′-methoxy-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 217 (2S,4S,5S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′- 577.1 biphenyl]-4-carbonyl)-4- (phenylsulfonyl)pyrrolidine-2-carboxylic acid 220 (2S,5R)-5-(2-chlorophenyl)-4-cyano-1-(2′- 461.9 methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 221 (2S,3R,5R)-5-(2-chlorophenyl)-3-cyano-1-(2′- 461.9 methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 224 (2S,5R)-1-(2-chloro-[1,1′-biphenyl]-4-carbonyl)-5- 441.3 (2-chlorophenyl)pyrrolidine-2-carboxylic acid 225 (2S,5R)-1-(2′-chloro-2-methoxy-[1,1′-biphenyl]-4- 471.3 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 226 (2S,5R)-5-(2-chlorophenyl)-1-(2′-(2- 481.0 methoxyethoxy)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 227 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- 426.9 methylthiophen-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 228 (2S,5R)-5-(2-chlorophenyl)-1-(2′,6′-dichloro-[1,1′- 475.8 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 229 (2S,5R)-1-(2′-chloro-4′-methoxy-[1,1′-biphenyl]-4- 471.3 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 230 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4- 438.9 (pyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid 231 (2S,5R)-1-(2′-carbamimidoyl-[1,1′-biphenyl]-4- 448.9 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 232 (2S,5R)-5-(2-fluorophenyl)-1-(2′-methoxy-[1,1′- 420.4 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 233 (2S,5R)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)- 416.5 5-(o-tolyl)pyrrolidine-2-carboxylic acid 234 (2S,5R)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)- 432.5 5-(2-methoxyphenyl)pyrrolidine-2-carboxylic acid 235 (2S,5R)-5-(2-chlorophenyl)-1-(2′- 450.9 (methoxymethyl)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 236 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6- 467.9 dimethoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 237 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(2- 468.9 methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 238 (2S,5R)-5-(2-chlorophenyl)-1-(4-(5- 438.9 methoxypyrazin-2-yl)benzoyl)pyrrolidine-2- carboxylic acid 239 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-(2- 481.9 methoxyethoxy)pyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 240 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3- 438.9 methoxypyrazin-2-yl)benzoyl)pyrrolidine-2- carboxylic acid 241 (2S,5R)-1-(4-(2-chloro-4- 486.4 (dimethylamino)pyrimidin-5-yl)benzoyl)-5-(2- chlorophenyl)pyrrolidine-2-carboxylic acid 242 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6- 468.9 dimethoxypyrimidin-4-yl)benzoyl)pyrrolidine-2- carboxylic acid 243 (2S,5R)-5-(2-chlorophenyl)-1-(2′-(dimethylamino)- 449.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 244 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- 438.9 methoxypyrimidin-4-yl)benzoyl)pyrrolidine-2- carboxylic acid 245 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(2- 468.9 methoxypyrimidin-4-yl)benzoyl)pyrrolidine-2- carboxylic acid 246 (2S,5R)-5-(2-fluorophenyl)-1-(4-(2- 421.4 methoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 247 (2S,5R)-1-(4-(2,4-dimethoxypyrimidin-5- 452.4 yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 248 (2S,5R)-5-(2-chlorophenyl)-1-(2-methyl-[1,1′- 420.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 249 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 250 (2S,5R)-5-(2-chlorophenyl)-1-(2′-(2-oxopyrrolidin- 490.0 1-yl)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 251 (2S,5R)-5-(2-chlorophenyl)-1-(5-phenylpyrazine-2- 408.9 carbonyl)pyrrolidine-2-carboxylic acid 252 (2S,5R)-5-(2-chlorophenyl)-1-(5-methoxy-6-(2- 467.9 methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid 253 (2S,5R)-5-(2-chlorophenyl)-1-(4-(5- 438.9 methoxypyrimidin-4-yl)benzoyl)pyrrolidine-2- carboxylic acid 254 (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridazin-4- 408.9 yl)benzoyl)pyrrolidine-2-carboxylic acid 255 (2S,5R)-1-(4-(1H-1,2,3-triazol-1-yl)benzoyl)-5-(2- 397.8 chlorophenyl)pyrrolidine-2-carboxylic acid 256 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4-(p-tolyl)-1H- 488.0 1,2,3-triazol-1-yl)benzoyl)pyrrolidine-2-carboxylic acid 257 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2- 443.9 methoxyphenyl)piperidine-4-carbonyl)pyrrolidine- 2-carboxylic acid 258 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- 444.9 methoxyphenyl)piperazine-1-carbonyl)pyrrolidine- 2-carboxylic acid 259 (2S,5R)-5-(2-chlorophenyl)-1-(1-(4- 445.9 methoxypyrimidin-5-yl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 260 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4- 446.9 methoxypyrimidin-5-yl)piperazine-1- carbonyl)pyrrolidine-2-carboxylic acid 261 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(4- 458.0 methylpiperidin-1-yl)benzoyl)pyrrolidine-2- carboxylic acid 262 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(1- 458.0 methylpiperidin-4-yl)benzoyl)pyrrolidine-2- carboxylic acid 263 (2S,5R)-5-(2-chlorophenyl)-1-(2-cyano-[1,1′- 431.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 264 (2S,5R)-5-(2-chlorophenyl)-1-(2-isobutoxy-[1,1′- 479.0 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 265 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4- 477.7 dichloropyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 266 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4- 498.9 dimethoxypyrimidin-5-yl)-3- methoxybenzoyl)pyrrolidine-2-carboxylic acid 267 (2S,5R)-1-(4-(2-chloro-4-methoxypyrimidin-5- 473.3 yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 268 (2S,3S,5S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′- 450.9 biphenyl]-4-carbonyl)-3-methylpyrrolidine-2- carboxylic acid 269 (2S,5R)-1-(4-(2,6-dimethoxypyridin-3-yl)benzoyl)- 451.5 5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid 270 (2S,5R)-1-(2′-(2-amino-2-oxoethoxy)-[1,1′- 479.9 biphenyl]-4-carbonyl)-5-(2- chlorophenyl)pyrrolidine-2-carboxylic acid 271 (2S,5R)-5-(2-chlorophenyl)-1-(2- 477.0 (cyclopropylmethoxy)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 272 (2S,5R)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)- 402.5 5-phenylpyrrolidine-2-carboxylic acid 273 (2S,5R)-5-(3-chlorophenyl)-1-(2′-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 274 (2S,5R)-5-(4-chlorophenyl)-1-(2′-methoxy-[1,1′- 436.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 275 (2S,5R)-5-(3-fluorophenyl)-1-(2′-methoxy-[1,1′- 420.4 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 276 (2S,5R)-5-(4-fluorophenyl)-1-(2′-methoxy-[1,1′- 420.4 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 278 (2S,5R)-4-acetyl-5-(2-chlorophenyl)-1-(2′- 478.9 methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 279 (2S,4S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′- 481.0 biphenyl]-4-carbonyl)-4- (methoxymethyl)pyrrolidine-2-carboxylic acid 280 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2- 438.9 methoxypyrimidin-4-yl)benzoyl)pyrrolidine-2- carboxylic acid 281 (2S,5R)-5-cyclohexyl-1-(2′-methoxy-[1,1′- 408.5 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 283 (2S,5R)-1-(4-(2-chloro-4-methoxypyrimidin-5- 473.3 yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 284 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3- 437.9 methoxypyridin-2-yl)benzoyl)pyrrolidine-2- carboxylic acid 285 (2R,5R)-5-(2-fluorophenyl)-1-(2′-methoxy-[1,1′- 420.4 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 286 (2S,5S)-5-(2-fluorophenyl)-1-(2′-methoxy-[1,1′- 420.4 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 287 (2R,5S)-5-(2-fluorophenyl)-1-(2′-methoxy-[1,1′- 420.4 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 288 (2S,5R)-5-(2-chlorophenyl)-1-(2-(trifluoromethyl)- 474.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 289 (2S,5R)-5-(2-chlorophenyl)-1-(2′,4′-difluoro-[1,1′- 442.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 290 (2S,5R)-5-(2-chlorophenyl)-1-(2-methyl-[1,1′- 420.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 291 (2S,5R)-5-(2,6-difluorophenyl)-1-(2′-methoxy- 438.4 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 292 (2S,5R)-5-(2,4-difluorophenyl)-1-(2′-methoxy- 438.4 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 293 (2S,5R)-5-(2,4-dichlorophenyl)-1-(2′-methoxy- 471.3 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 294 (2S,5R)-5-isobutyl-1-(2′-methoxy-[1,1′-biphenyl]- 382.5 4-carbonyl)pyrrolidine-2-carboxylic acid 295 (2S,5R)-5-isopropyl-1-(2′-methoxy-[1,1′-biphenyl]- 368.4 4-carbonyl)pyrrolidine-2-carboxylic acid 296 (2S,5R)-1-(3-chloro-4-(pyrimidin-4-yl)benzoyl)-5- 443.3 (2-chlorophenyl)pyrrolidine-2-carboxylic acid 297 (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-[1,1′- 424.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 298 (2S,5R)-5-(2-chlorophenyl)-1-(2′-fluoro-4′- 454.9 methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 299 (2S,5R)-5-(2-chlorophenyl)-1-(4′-fluoro-2′- 454.9 methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 300 (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-ethoxypyridin- 451.9 3-yl)benzoyl)pyrrolidine-2-carboxylic acid 301 (2S,5R)-5-(2-chlorophenyl)-1-(4-(6- 465.9 isopropoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 302 (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-methoxy-2- 451.9 methylpyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 303 (2S,5R)-1-(3-chloro-4-(2-methoxypyrimidin-4- 473.3 yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 304 (2S,5R)-1-(3-chloro-4-(pyrimidin-5-yl)benzoyl)-5- 443.3 (2-chlorophenyl)pyrrolidine-2-carboxylic acid 305 (2S,5R)-5-(2-chlorophenyl)-4-cyano-1-(2′- 475.9 methoxy-[1,1′-biphenyl]-4-carbonyl)-3- methylpyrrolidine-2-carboxylic acid 306 (2S,4S,5R)-5-(2-chlorophenyl)-4-cyano-1-(2′- 475.9 methoxy-[1,1′-biphenyl]-4-carbonyl)-4- methylpyrrolidine-2-carboxylic acid 307 (2S,5R)-5-(2-chlorophenyl)-1-(2′,3′-dimethoxy- 466.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 308 (2S,5R)-5-(2-chlorophenyl)-1-(3′,4′-dimethoxy- 466.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 309 (2S,5R)-5-(2-chlorophenyl)-1-(2′,3′,4′-trimethoxy- 497.0 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 310 (2S,5R)-5-(2-chlorophenyl)-1-(2′,3′,6′-trimethoxy- 497.0 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 311 (2S,5R)-5-(2-chlorophenyl)-1-(3′,5′-dimethoxy- 466.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 312 (2S,5R)-5-(2-chlorophenyl)-1-(2′,5′-dimethoxy- 466.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 313 (2S,5R)-5-(2-chlorophenyl)-1-(2′-isopropyl-[1,1′- 449.0 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 314 (2S,5R)-1-(2,2′-dimethoxy-[1,1′-biphenyl]-4- 450.5 carbonyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 315 (2S,5R)-1-(2-fluoro-2′-methoxy-[1,1′-biphenyl]-4- 438.4 carbonyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 316 (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-2′- 454.9 methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 318 (2S,5R)-5-cyclopentyl-1-(2′-methoxy-[1,1′- 394.5 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 319 (2S,5R)-5-(2-chlorophenyl)-1-(2′-ethyl-[1,1′- 434.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 320 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6- 435.9 dimethylpyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 321 (2S,5R)-1-(4-(2,4-bis(benzyloxy)pyrimidin-5- 621.1 yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 322 (2S,5R)-1-([1,1′: 4′,1″-terphenyl]-4-carbonyl)-5-(2- 483.0 chlorophenyl)pyrrolidine-2-carboxylic acid 323 (2S,5R)-5-(2-chlorophenyl)-1-(4′-propyl-[1,1′- 449.0 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 324 (2S,5R)-1-(4′-(tert-butyl)-[1,1′-biphenyl]-4- 463.0 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 325 (2S,5R)-1-(3-chloro-4-(2,4-dimethoxypyrimidin-5- 503.3 yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 326 (2S,5R)-5-(2-chlorophenyl)-1-(5-(2- 438.9 methoxyphenyl)pyrazine-2-carbonyl)pyrrolidine-2- carboxylic acid 327 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(4- 467.9 methoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 328 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(6- 467.9 methoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 329 (2S,5R)-1-(3-chloro-4-(2-methoxypyrimidin-5- 473.3 yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 330 (2S,5R)-1-(3-chloro-4-(6-methoxypyridin-3- 472.3 yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 331 (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-(4- 531.5 chlorophenyl)thiazol-2-yl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 332 (2S,5R)-5-(2-fluorophenyl)-1-(5-methoxy-6-(2- 451.5 methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid 333 (2S,5R)-1-(1-(benzo[d]oxazol-2-yl)piperidine-4- 454.9 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 334 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4- 429.9 (pyrrolidin-1-yl)benzoyl)pyrrolidine-2-carboxylic acid 335 (2S,5R)-5-(2-chlorophenyl)-1-(5-methoxy-6-(2- 467.9 methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid 336 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2- 443.9 methoxyphenyl)piperidine-4-carbonyl)pyrrolidine- 2-carboxylic acid 337 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4- 498.9 dimethoxypyrimidin-5-yl)-3- methoxybenzoyl)pyrrolidine-2-carboxylic acid 338 (2S,5R)-5-(2-bromophenyl)-1-(2′-methoxy-[1,1′- 481.4 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 339 (2S,5R)-5-(2-chlorophenyl)-1-(3′-cyano-[1,1′- 431.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 340 (2S,5R)-5-(2-chlorophenyl)-1-(3′-cyano-2′- 461.9 methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 341 (2S,5R)-5-(2-chlorophenyl)-1-(3′-cyano-2′,4′- 627.9 bis(2,2,2-trifluoroethoxy)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 342 (2S,5R)-1-(3′-amino-2′-methyl-[1,1′-biphenyl]-4- 435.9 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 343 (2S,5R)-5-(2-chlorophenyl)-1-(2′-methyl-3′- 514.0 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 344 (2S,5R)-1-(3′-acetamido-2′-methyl-[1,1′-biphenyl]- 478.0 4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 345 (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′- 461.9 methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 346 (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′-methyl- 445.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 347 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6- 467.9 dimethoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 348 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3,6- 468.9 dimethoxypyridazin-4-yl)benzoyl)pyrrolidine-2- carboxylic acid 349 (2S,5S)-5-isopentyl-1-(2′-methoxy-[1,1′-biphenyl]- 396.5 4-carbonyl)pyrrolidine-2-carboxylic acid 350 (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-4′- 530.0 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 351 (2S,5R)-1-(4′-acetamido-2′-methoxy-[1,1′- 494.0 biphenyl]-4-carbonyl)-5-(2- chlorophenyl)pyrrolidine-2-carboxylic acid 352 (2S,5R)-1-(3′-carbamimidoyl-[1,1′-biphenyl]-4- 448.9 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 353 (2S,5R)-5-(2-chlorophenyl)-1-(3′-((E)-N′- 464.9 hydroxycarbamimidoyl)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 354 (2S,5R)-5-(2-fluorophenyl)-1-(2′-methoxy-4′- 513.6 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 355 (2S,5R)-5-(2,4-difluorophenyl)-1-(4-(2,6- 469.4 dimethoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 356 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(5- 467.9 methoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 357 (2S,5R)-1-(4′-amino-2′-methoxy-[1,1′-biphenyl]-4- 451.9 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 358 (2S,5R)-5-(2-chlorophenyl)-1-(2′,3,6′-trimethoxy- 498.9 [2,3′-bipyridine]-5-carbonyl)pyrrolidine-2- carboxylic acid 359 (2S,5R)-1-(3′-carbamoyl-[1,1′-biphenyl]-4- 449.9 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 360 (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′,3′- 491.9 dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine- 2-carboxylic acid 361 (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-4′,5′- 491.9 dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine- 2-carboxylic acid 362 (2S,5R)-5-(2-chlorophenyl)-1-(3′,4′,5′-trimethoxy- 497.0 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 363 (2S,5R)-5-(2-chlorophenyl)-1-(2′-(cyanomethyl)- 506.0 4′,5′-dimethoxy-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 364 (2S,5R)-5-(2-chlorophenyl)-1-(3′,4′-dicyano-[1,1′- 456.9 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 365 (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′-fluoro- 449.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 366 (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-3′,4′- 484.9 dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine- 2-carboxylic acid 367 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6- 485.9 dimethoxypyridin-3-yl)-3- fluorobenzoyl)pyrrolidine-2-carboxylic acid 368 (2S,5R)-5-(2-chlorophenyl)-1-(3-fluoro-4-(6- 455.9 methoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 369 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-cyano-4- 506.9 (trifluoromethyl)phenyl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 370 (2S,5R)-1-(1-(2-chloro-4- 516.4 (trifluoromethyl)phenyl)piperidine-4-carbonyl)-5- (2-chlorophenyl)pyrrolidine-2-carboxylic acid 371 (2S,5R)-1-(5′-cyano-2′-methoxy-[1,1′-biphenyl]-4- 445.5 carbonyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 372 (2S,5R)-1-(4-(2,6-dimethoxypyridin-3-yl)-3- 469.4 fluorobenzoyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 373 (2S,5R)-1-(3-fluoro-4-(6-methoxypyridin-3- 439.4 yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 374 (2S,5R)-1-(4-(3,6-dimethoxypyridazin-4- 452.4 yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 375 (2S,5R)-1-(3′-carbamoyl-4′-cyano-[1,1′-biphenyl]- 474.9 4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 376 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-nitro-4- 526.9 (trifluoromethyl)phenyl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 377 (2S,5R)-5-(2-chlorophenyl)-1-(1-(4- 608.1 (morpholinosulfonyl)-2-nitrophenyl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 378 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-nitro-4- 606.1 (piperidin-1-ylsulfonyl)phenyl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 379 (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-(N,N- 594.1 diethylsulfamoyl)-2-nitrophenyl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 380 (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-methyl-2- 472.9 nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2- carboxylic acid 381 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-cyano-4- 483.9 nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2- carboxylic acid 382 (2S,5R)-5-(2-chlorophenyl)-1-(1-(4- 458.9 nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2- carboxylic acid 383 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-fluoro-4- 476.9 nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2- carboxylic acid 384 (2S,5R)-5-(2-chlorophenyl)-1-(1-(3-methoxy-4- 488.9 nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2- carboxylic acid 385 (2S,5R)-1-(1-(5-chloro-2-nitrophenyl)piperidine-4- 493.4 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 386 (2S,5R)-5-(2-cyanophenyl)-1-(2′-methoxy-[1,1′- 427.5 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 387 (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-4′- 461.9 methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2- carboxylic acid 388 (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-4′- 518.0 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 389 (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-3′- 518.0 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 390 (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-2-fluoro- 449.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 391 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-cyano-4- 532.0 (methylsulfonamido)phenyl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 392 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-cyano-4- 468.9 methoxyphenyl)piperidine-4-carbonyl)pyrrolidine- 2-carboxylic acid 393 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2- 575.0 (methylsulfonamido)-4- (trifluoromethyl)phenyl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 394 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2- 458.9 nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2- carboxylic acid 395 (2S,5R)-5-(2-chlorophenyl)-1-(1-(4- 438.9 cyanophenyl)piperidine-4-carbonyl)pyrrolidine-2- carboxylic acid 396 (2S,5R)-5-(3,5-difluorophenyl)-1-(2′-methoxy- 438.4 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 397 (2S,5R)-5-(3,4-difluorophenyl)-1-(2′-methoxy- 438.4 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 398 (2S,5R)-5-(2,3-difluorophenyl)-1-(2′-methoxy- 438.4 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 399 (2S,5R)-5-(2,5-difluorophenyl)-1-(2′-methoxy- 438.4 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 400 (2S,5R)-5-([1,1′-biphenyl]-2-yl)-1-(2′-methoxy- 478.6 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 401 (2S,5R)-1-(2′-cyano-4′-methoxy-[1,1′-biphenyl]-4- 445.5 carbonyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 402 (2S,5R)-5-(4-cyanophenyl)-1-(2′-methoxy-[1,1′- 427.5 biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 403 (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-methyl-4- 552.0 (phenylsulfonyl)-1H-1,2,3-triazol-1- yl)benzoyl)pyrrolidine-2-carboxylic acid 404 (2S,5R)-5-(2-chlorophenyl)-1-(3′-cyano-4′-fluoro- 449.9 [1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 405 (2S,5R)-1-(2′-chloro-5′-cyano-[1,1′-biphenyl]-4- 466.3 carbonyl)-5-(2-chlorophenyl)pyrrolidine-2- carboxylic acid 406 (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-4′- 499.9 (trifluoromethyl)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 407 (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-methoxy-4- 511.9 (trifluoromethyl)phenyl)piperidine-4- carbonyl)pyrrolidine-2-carboxylic acid 408 (2S,5R)-5-(2-chlorophenyl)-1-(2′-methyl-3′-(N- 528.0 methylmethylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 409 (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-4′-(N- 544.0 methylmethylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 410 (2S,5R)-5-(2-chlorophenyl)-1-(6-(5-cyano-2- 492.9 methoxyphenyl)-5-methoxynicotinoyl)pyrrolidine- 2-carboxylic acid 411 (2S,5R)-5-(2-chlorophenyl)-1-(6-(2,4- 497.9 dimethoxyphenyl)-5- methoxynicotinoyl)pyrrolidine-2-carboxylic acid 412 (2S,5R)-5-(2-chlorophenyl)-1-(6-(2,4- 467.9 dimethoxyphenyl)nicotinoyl)pyrrolidine-2- carboxylic acid 413 (2S,5R)-1-(2′-cyano-4′-(trifluoromethyl)-[1,1′- 483.4 biphenyl]-4-carbonyl)-5-(2- fluorophenyl)pyrrolidine-2-carboxylic acid 414 (2S,5R)-1-(3′-cyano-4′-fluoro-[1,1′-biphenyl]-4- 433.4 carbonyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 415 (2S,5R)-1-(2′-chloro-5′-cyano-[1,1′-biphenyl]-4- 449.9 carbonyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 416 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3,6- 486.9 dimethoxypyridazin-4-yl)-3- fluorobenzoyl)pyrrolidine-2-carboxylic acid 417 (2S,5R)-5-(2-fluorophenyl)-1-(2′-methyl-3′-(N- 511.6 methylmethylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 418 (2S,5R)-5-(2-fluorophenyl)-1-(2′-methoxy-4′-(N- 527.6 methylmethylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 419 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6- 468.9 dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 420 (2S,5R)-5-(2,3-difluorophenyl)-1-(4-(2,4- 470.4 dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 421 (2S,5R)-1-(5′-cyano-2′-methyl-[1,1′-biphenyl]-4- 447.4 carbonyl)-5-(2,3-difluorophenyl)pyrrolidine-2- carboxylic acid 422 (2S,5R)-5-(2,3-difluorophenyl)-1-(2′-methoxy-4′- 531.5 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 423 (2S,5R)-5-(2,3-difluorophenyl)-1-(2′-methyl-3′- 515.5 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 424 (2S,5R)-5-(2-fluorophenyl)-1-(2′-methyl-3′- 497.6 (methylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 425 (2S,5R)-5-(2,3-difluorophenyl)-1-(4-(2- 439.4 methoxypyridin-3-yl)benzoyl)pyrrolidine-2- carboxylic acid 426 (2S,5R)-5-(2,3-difluorophenyl)-1-(3-methoxy-4-(2- 470.4 methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 427 (2S,5R)-5-(2-fluorophenyl)-1-(3-methoxy-4-(2- 452.4 methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2- carboxylic acid 428 (2S,5R)-5-(2,3-difluorophenyl)-1-(4-(3,6- 470.4 dimethoxypyridazin-4-yl)benzoyl)pyrrolidine-2- carboxylic acid 429 (2S,5R)-1-(5′-cyano-2′-methoxy-[1,1′-biphenyl]-4- 463.4 carbonyl)-5-(2,3-difluorophenyl)pyrrolidine-2- carboxylic acid 430 (2S,5R)-1-(5′-cyano-2′-methyl-[1,1′-biphenyl]-4- 429.5 carbonyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid 431 (2S,5R)-5-(2,3-difluorophenyl)-1-(4-(3,6- 488.4 dimethoxypyridazin-4-yl)-3- fluorobenzoyl)pyrrolidine-2-carboxylic acid 432 (2S,5R)-1-(4-(3,6-dimethoxypyridazin-4-yl)-3- 470.4 fluorobenzoyl)-5-(2-fluorophenyl)pyrrolidine-2- carboxylic acid

The compounds of table 1 were named using ChemDraw Ultra 12 purchased from CambridgeSoft (Cambridge, Mass., USA).

The compounds of formula I can be prepared by different ways with reactions known by the person skilled in the art. Reaction schemes as described in the example section illustrate by way of example different possible approaches.

The invention further provides processes for the preparation of compounds of the invention or a pharmaceutically acceptable salts or solvates thereof.

In one embodiment, the invention further provides a process for the preparation of a compound of formula Ib-1b′

wherein Ar² is as defined defined above in respect to formula Ib-1b′;

-   Ar¹ is 2-chlorophenyl, 2-fluorophenyl, 2,3-difluorophenyl; -   R¹, R², R³, R^(3′), R⁴ and R are H; -   D is C═O; -   L² is a single bond;     which consists of:

a) the coupling of a compound of formula A

wherein

-   R⁸ is Cl or F and R⁹ is H, or R⁸ and R⁹ are both F; -   R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl,     methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl,     2-trimethylsilylethyl, tert-butyldiphenylsilyl, preferably R is     methyl, ethyl, or tert-butyl;

with a compound of formula B

wherein:

-   Ar² is as defined defined above in respect to formula Ib-1b′; -   R″ is Cl or OL wherein L is a carboxylic acid activating group,     followed by

b) a alkaline or acidic treatment, hydrogenolysis or treatment with fluoride of the ester intermediate obtained in step a);

step b) being optionally followed by conversion of a compound of formula Ib-1b′ to a pharmaceutically acceptable salt or solvate thereof.

In another embodiment the invention further provides a process for the preparation of a compound of formula Ib-1b′

wherein Ar¹R³, R^(3′), R⁴ are as defined above in respect to formula Ib-1b′;

-   R¹, R², and R are H; -   D is C═O; -   L² is a single bond; -   Ar² is selected from 4′-(2-methoxy-4-methylsulfonyl-1,1′-biphenyl),     4′-(2-methyl-3-methylsulfonylamino-1,1′-biphenyl),     4-(2-methoxypyridin-3-yl)phenyl,     4-(2,6-dimethoxypyrimidin-5-yl)phenyl,     3-methoxy-4-(2-methoxypyrimidin-5-yl)phenyl,     4-(3,6-dimethoxypyridazin-5-yl)phenyl,     4′-(5-cyano-2-methoxy-1,1′-biphenyl),     4′-(5-cyano-2-methyl-1,1′-biphenyl),     3-fluoro-4-(3,6-dimethoxypyridazin-5-yl)phenyl,     (4-(4-methoxypyridin-3-yl)phenyl),     (4′-(methylsulfonamido)-[1,1′-biphenyl]-4-yl),     (3′-(methylsulfonamido)-[1,1′-biphenyl]-4-yl),     (4-(2,4-dimethoxypyrimidin-5-yl)phenyl),     (5-methoxy-6-phenylpyridin-3-yl),     (4-(4-methoxypyrimidin-5-yl)phenyl),     (2,2′-dimethoxy-[1,1′-biphenyl]-4-yl),     (3-methoxy-4-(4-methoxypyridin-3-yl)phenyl),     (4-(2,4-dimethoxypyrimidin-5-yl)-3-methoxyphenyl),     (4′-acetamido-2′-methoxy-[1,1′-biphenyl]-4-yl),     (2′-cyano-4′,5′-dimethoxy-[1,1′-biphenyl]-4-yl),     (2′-methoxy-4′-(N-methylmethylsulfonamido)-[1,1′-biphenyl]-4-yl),     (6-(2,4-dimethoxyphenyl)pyridin-3-yl),     (4-(4,6-dimethoxypyrimidin-5-yl)phenyl),     (4-(3-methoxypyridin-4-yl)phenyl);     which consists of:

a) the coupling of a compound of formula C

wherein:

-   Ar¹, R³, R^(3′) and R⁴ e are as defined above in respect to formula     Ib-1b′; -   R is methyl, ethyl, tert-butyl, benzyl, allyl, phenacyl,     methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl,     2-trimethylsilylethyl, tert-butyldiphenylsilyl, preferably R is     methyl, ethyl, or tert-butyl,

with a compound of formula D

wherein

-   R″ is Cl or OL, wherein L is a carboxylic acid activating group; -   A⁰, A^(0′), A¹, A², A³, A⁴ and A⁵ are selected from the combinations     1 to 24:

Combination n^(o) A⁰ A^(0′) A¹ A² A³ A⁴ A⁵ 1 CH CH C—OCH₃ CH C—NHSO₂CH₃ CH CH 2 CH CH C—CH₃ C—NHSO₂CH₃ CH CH CH 3 CH CH C—OCH₃ N CH CH CH 4 CH CH C—OCH₃ N C—OCH₃ N CH 5 C—OCH₃ CH CH N C—OCH₃ N CH 6 CH CH C—OCH₃ N N C—OCH₃ CH 7 CH CH C—OCH₃ CH CH C—CN CH 8 CH CH C—CH₃ CH CH C—CN CH 9 C—F CH C—OCH₃ N N C—OCH₃ CH 10 CH CH CH N CH CH C—OCH₃ 11 CH CH CH CH C—NHSO₂CH₃ CH CH 12 CH CH CH C—NHSO₂CH₃ CH CH CH 13 CH CH CH N C—OCH₃ N C—OCH₃ 14 N C—OCH₃ CH CH CH CH CH 15 CH CH C—OCH₃ N CH N CH 16 CH C—OCH₃ C—OCH₃ CH CH CH CH 17 C—OCH₃ CH CH N CH CH C—OCH₃ 18 C—OCH₃ CH C—OCH₃ N C—OCH₃ N CH 19 CH CH C—OCH₃ CH C—NHCOCH₃ CH CH 20 CH CH C—CN CH C—OCH₃ C—OCH₃ CH 21 CH CH C—OCH₃ CH C—N(CH₃)SO₂CH₃ CH CH 22 N CH C—OCH₃ CH C—OCH₃ CH CH 23 CH CH C—OCH₃ N CH N C—OCH₃ 24 CH CH C—OCH₃ CH N CH CH followed by

b) an alkaline or acidic treatment, a hydrogenolysis or a treatment with fluoride of the ester intermediate obtained in step a);

step b) being optionally followed by conversion of a compound of formula Ib-1b′ to a pharmaceutically acceptable salt or solvate thereof.

In yet another embodiment, the invention further provides a process for the preparation of a compound of the formula Ib-1h″

wherein

-   R⁸ is F or Cl and R⁹ is H, or both R⁸ and R⁹ are F; -   R is H; -   A⁰, A^(0′), A¹, A², A³, A⁴ and A⁵ are selected from the combinations     1 to 24:

Combination n^(o) A⁰ A^(0′) A¹ A² A³ A⁴ A⁵ 1 CH CH C—OCH₃ CH C—NHSO₂CH₃ CH CH 2 CH CH C—CH₃ C—NHSO₂CH₃ CH CH CH 3 CH CH C—OCH₃ N CH CH CH 4 CH CH C—OCH₃ N C—OCH₃ N CH 5 C—OCH₃ CH CH N C—OCH₃ N CH 6 CH CH C—OCH₃ N N C—OCH₃ CH 7 CH CH C—OCH₃ CH CH C—CN CH 8 CH CH C—CH₃ CH CH C—CN CH 9 C—F CH C—OCH₃ N N C—OCH₃ CH 10 CH CH CH N CH CH C—OCH₃ 11 CH CH CH CH C—NHSO₂CH₃ CH CH 12 CH CH CH C—NHSO₂CH₃ CH CH CH 13 CH CH CH N C—OCH₃ N C—OCH₃ 14 N C—OCH₃ CH CH CH CH CH 15 CH CH C—OCH₃ N CH N CH 16 CH C—OCH₃ C—OCH₃ CH CH CH CH 17 C—OCH₃ CH CH N CH CH C—OCH₃ 18 C—OCH₃ CH C—OCH₃ N C—OCH₃ N CH 19 CH CH C—OCH₃ CH C—NHCOCH₃ CH CH 20 CH CH C—CN CH C—OCH₃ C—OCH₃ CH 21 CH CH C—OCH₃ CH C—N(CH₃)SO₂CH₃ CH CH 22 N CH C—OCH₃ CH C—OCH₃ CH CH 23 CH CH C—OCH₃ N CH N C—OCH₃ 24 CH CH C—OCH3 CH N CH CH which consists of

a) the coupling of a compound of formula A as defined above with a compound of formula B as defined above, followed by

b) an alkaline or acidic treatment, a hydrogenolysis or a treatment with fluoride of the ester intermediate obtained in step a);

step b) being optionally followed by conversion of a compound of formula Ib-1h″ to a pharmaceutically acceptable salt or solvate thereof.

In one variant of the process for the preparation of a compound of formula Ib-1h″ as described above, the compound of formula Ib-1h″ is selected from:

122 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-methoxypyridin-3- yl)benzoyl)pyrrolidine-2-carboxylic acid 125 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4-methoxypyridin-3- yl)benzoyl)pyrrolidine-2-carboxylic acid 129 (2S,5R)-5-(2-chlorophenyl)-1-(4′-(methylsulfonamido)-[1,1′- biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 130 (2S,5R)-5-(2-chlorophenyl)-1-(3′-(methylsulfonamido)-[1,1′- biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 161 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4-dimethoxypyrimidin-5- yl)benzoyl)pyrrolidine-2-carboxylic acid 191 (2S,5R)-5-(2-chlorophenyl)-1-(5-methoxy-6- phenylnicotinoyl)pyrrolidine-2-carboxylic acid 193 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3-methoxypyridin-4- yl)benzoyl)pyrrolidine-2-carboxylic acid 203 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4-methoxypyrimidin-5- yl)benzoyl)pyrrolidine-2-carboxylic acid 237 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(2- methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid 246 (2S,5R)-5-(2-fluorophenyl)-1-(4-(2-methoxypyridin-3- yl)benzoyl)pyrrolidine-2-carboxylic acid 247 (2S,5R)-1-(4-(2,4-dimethoxypyrimidin-5-yl)benzoyl)-5-(2- fluorophenyl)pyrrolidine-2-carboxylic acid 314 (2S,5R)-1-(2,2′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2- fluorophenyl)pyrrolidine-2-carboxylic acid 327 (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(4- methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid 337 (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4-dimethoxypyrimidin-5- yl)-3-methoxybenzoyl)pyrrolidine-2-carboxylic acid 343 (2S,5R)-5-(2-chlorophenyl)-1-(2′-methyl-3′- (methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine- 2-carboxylic acid 345 (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′-methoxy-[1,1′- biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 346 (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′-methyl-[1,1′- biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 348 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3,6-dimethoxypyridazin-4- yl)benzoyl)pyrrolidine-2-carboxylic acid 350 (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-4′- (methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine- 2-carboxylic acid 351 (2S,5R)-1-(4′-acetamido-2′-methoxy-[1,1′-biphenyl]-4- carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid 354 (2S,5R)-5-(2-fluorophenyl)-1-(2′-methoxy-4′- (methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine- 2-carboxylic acid 361 (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-4′,5′-dimethoxy-[1,1′- biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid 371 (2S,5R)-1-(5′-cyano-2′-methoxy-[1,1′-biphenyl]-4-carbonyl)- 5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid 374 (2S,5R)-1-(4-(3,6-dimethoxypyridazin-4-yl)benzoyl)-5-(2- fluorophenyl)pyrrolidine-2-carboxylic acid 409 (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-4′-(N- methylmethylsulfonamido)-[1,1′-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid 412 (2S,5R)-5-(2-chlorophenyl)-1-(6-(2,4- dimethoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid 416 (2S,5R)-5-(2-chlorophenyl)-1-(4-(3,6-dimethoxypyridazin-4- yl)-3-fluorobenzoyl)pyrrolidine-2-carboxylic acid 419 (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6-dimethoxypyrimidin-5- yl)benzoyl)pyrrolidine-2-carboxylic acid 420 (2S,5R)-5-(2,3-difluorophenyl)-1-(4-(2,4- dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid 421 (2S,5R)-1-(5′-cyano-2′-methyl-[1,1′-biphenyl]-4-carbonyl)-5- (2,3-difluorophenyl)pyrrolidine-2-carboxylic acid

Suitable carboxylic acid activating groups L for use in the above processes are benzotriazol-1-yl, 7-azabenzotriazol-1-yl, imidazol-1-yl, preferably 7-azabenzotriazol-1-yl.

In a typical procedure applicable to all of the aforementioned processes, the coupling reactions of a compound of formula B or D wherein R″ is OL, are done in the presence of a base such as triethylamine, diisopropylethylamine, preferably diisopropylethylamine, in a suitable solvent such as MeCN, DMF, DCM, preferably MeCN, at a suitable temperature ranging from room temperature to the boiling point of the solvent used, preferably at room temperature. Intermediates of formulae B and D are generated in situ from their corresponding carboxylic acid precursor which is reacted with HOBt, HOBt hydrate, HATU, CDI, pentafluorophenol, preferably with HATU. Preferably, the coupling with an activated carboxylic acid is made using HATU and DIEA in MeCN at room temperature.

In a typical procedure applicable to all of the above-mentioned processes, the coupling reactions of a compound of formula B or D wherein R is Cl, are done in the presence of a base such as triethylamine, diisopropylethylamine, preferably triethylamine, in a suitable solvent such as MeCN, DMF, DCM preferably DCM, at a suitable temperature ranging from room temperature to the boiling point of the solvent used, preferably at room temperature. Preferably, the coupling with an acyl chloride is made using triethylamine in DCM at room temperature.

In a typical procedure applicable to all of the aforementioned processes, the alkaline treatment of the intermediates obtained after coupling step a) and wherein R is methyl or ethyl, are done in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, trimethyltin hydroxide, preferably lithium hydroxide, in a suitable solvent such as a 1/1 (v/v) mixture of water and THF, DCE, at a suitable temperature ranging from room temperature to the boiling point of the solvent used, preferably at room temperature.

In a typical procedure applicable to all of the above-mentioned processes, the acidic treatment of the intermediates obtained after coupling step a) and wherein R is tert-butyl, are done in the presence of a suitable acid such as HCl or TFA, in a suitable solvent such as DCM, dioxane, or in a miscible mixture of said solvents, at room temperature.

Those skilled in the art will appreciate that typical procedures applicable to all of the above-mentioned processes for step b) and wherein R is benzyl, allyl, phenacyl, methoxymethyl, methylthio methyl, 2-methoxyethoxymethyl, 2-trimethylsilylethyl or tert-butyldiphenylsilyl are well known and are indeed reported in Koscienski P. J., Protecting Groups 3^(rd) edition, Thieme, 2005, 394-450.

In a particular embodiment, useful intermediates for the preparation of compounds of the invention are those of formula E:

wherein

-   R⁸ is Cl or F and R⁹ is H, or R⁸ and R⁹ are both F; -   R is methyl, ethyl, benzyl, allyl, phenacyl, methoxymethyl,     methylthiomethyl, 2-methoxyethoxymethyl, 2-trimethylsilyl ethyl,     tert-butyldiphenylsilyl or R is tert-butyl when R⁸ is F.

Preferred compounds of formula E are those wherein R is methyl, ethyl, or R is tert-butyl when R⁸ is F.

In a particular embodiment, useful intermediates for the preparation of compounds of the invention are those of formula F:

wherein

-   R′ is OH or Cl; -   A⁰, A^(0′), A¹, A², A³, A⁴ and A⁵ are selected from the combinations     1 to 7, 9, 10, 13 to 15, 17 to 21, 23 and 24:

Combination n^(o) A⁰ A^(0′) A¹ A² A³ A⁴ A⁵ 1 CH CH C—OCH₃ CH C—NHSO₂CH₃ CH CH 2 CH CH C—CH₃ C—NHSO₂CH₃ CH CH CH 3 CH CH C—OCH₃ N CH CH CH 4 CH CH C—OCH₃ N C—OCH₃ N CH 5 C—OCH₃ CH CH N C—OCH₃ N CH 6 CH CH C—OCH₃ N N C—OCH₃ CH 7 CH CH C—OCH₃ CH CH C—CN CH 9 C—F CH C—OCH₃ N N C—OCH₃ CH 10 CH CH CH N CH CH C—OCH₃ 13 CH CH CH N C—OCH₃ N C—OCH₃ 14 N C—OCH₃ CH CH CH CH CH 15 CH CH C—OCH₃ N CH N CH 17 C—OCH₃ CH CH N CH CH C—OCH₃ 18 C—OCH₃ CH C—OCH₃ N C—OCH₃ N CH 19 CH CH C—OCH₃ CH C—NHCOCH₃ CH CH 20 CH CH C—CN CH C—OCH₃ C—OCH₃ CH 21 CH CH C—OCH₃ CH C—N(CH₃)SO₂CH₃ CH CH 23 CH CH C—OCH₃ N CH N C—OCH₃ 24 CH CH C—OCH₃ CH N CH CH

The invention further provides the use of the compounds of the invention or pharmaceutically acceptable salts, solvates or prodrugs thereof as agonists or partial agonists of G-protein coupled receptor 43 (GPR43).

Accordingly, in a particularly preferred embodiment, the invention relates to the use of compounds of formula I and subformulae in particular those of table 1 above, or pharmaceutically acceptable salts, solvates and prodrugs thereof, as GPR43 agonists or partial agonists.

[Applications]

The compounds of the invention are therefore useful in the prevention and/or treatment of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

Preferred diseases are type II diabetes, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

In a particular preferred embodiment the diseases are type II diabetes and a lipid disorder such as dyslipidemia.

The invention also provides for a method for delaying in patient the onset of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH) comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof to a patient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably a human.

The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvates thereof for the manufacture of a medicament for use in treating a patient and/or preventing a patient from developing a disease selected from the group consisting of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

Preferably, the patient is a warm-blooded animal, more preferably a human.

According to a further feature of the present invention there is provided a method for modulating GPR43 receptor activity, in a patient, preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said animal an effective amount of compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

According to one embodiment, the compounds of the invention, their pharmaceutical acceptable salts, solvates or prodrugs may be administered as part of a combination therapy. Thus, are included within the scope of the present invention embodiments comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients. Such multiple drug regimens, often referred to as combination therapy, may be used in the treatment and/or prevention of any of the diseases or conditions mediated by or associated with GPR43 receptor modulation, particularly type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH). The use of such combinations of therapeutic agents is especially pertinent with respect to the treatment of the above-mentioned list of diseases within a patient in need of treatment or one at risk of becoming such a patient.

In addition to the requirement of therapeutic efficacy, which may necessitate the use of active agents in addition to the GPR43 agonist or partial agonist compounds of Formula I or their pharmaceutical acceptable salts, solvates or prodrugs thereof, there may be additional rationales which compel or highly recommend the use of combinations of drugs involving active ingredients which represent adjunct therapy, i.e., which complement and supplement the function performed by the GPR43 receptor agonist or partial agonist compounds of the present invention. Suitable supplementary therapeutic agents used for the purpose of auxiliary treatment include drugs which, instead of directly treating or preventing a disease or condition mediated by or associated with GPR43 receptor modulation, treat diseases or conditions which directly result from or indirectly accompany the basic or underlying GPR43 receptor modulated disease or condition.

Thus, the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of Formula I or their pharmaceutical acceptable salts, solvates or prodrugs thereof in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of Formula I or their pharmaceutically acceptable salts, solvates and prodrugs are coadministered in combination with one or more other therapeutic agents such as those described in detail further herein.

Examples of other active ingredients that may be administered in combination with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and either administered separately or in the same pharmaceutical composition, include but are not limited to:

-   -   (a) PPARγ agonists and partial agonists, including both         glitazones and non-glitazones (e.g. troglitazone, pioglitazone,         englitazone, MCC-555, rosiglitazone, balaglitazone,         netoglitazone, T-131, LY-300512 and LY-818;     -   (b) Biguanides such as metformin and phenformin;     -   (c) Protein tyrosine phosphatase-1B (PTP-1B) inhibitors,     -   (d) Dipeptidyl peptidase IV (DP-IV) inhibitor, such as MK-0431         and LAF-237;     -   (e) Insulin or insulin mimetics;     -   (f) Sulfonylureas such as tolbutamide and glipizide or related         materials;     -   (g) α-glucosidase inhibitors (such as acarbose);     -   (h) agents which improve a patient's lipid profile such as (i)         HMG-CoA reductase inhibitors (lovastatin, simvastatin,         rosuvastatin, pravastatin, fluvastatin, atorvastatin,         rivastatin, itavastatin, ZD-4522 and other statins), (ii) bile         acid sequestrants (cholestyramine, colestipol and         dialkylaminoalkyl derivatives of a cross-linked dextran), (iii)         nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARα         agonists such as fenofibric acid derivatives (gemfibrozil,         clofibrate, fenofibrate and bezafibrate), (v) cholesterol         absorption inhibitors such as for example ezetimibe, (vi) acyl         CoA: cholesterol acyltransferase (ACAT) inhibitors such as         avasimibe, (vii) CETP inhibitors such as torcetrapib and (viii)         phenolic anti-oxidants such as probucol;     -   (i) PPARα/γ dual agonists such as muraglitazar, tesaglitazar,         farglitazar and JT-501;     -   (j) PPARδ agonists such those disclosed in WO97/28149;     -   (k) Antiobesity compounds such as fenfluramine, dextenfluramine,         phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors,         MC4R agonists, cannabinoid receptor 1 antagonists/inverse         agonists and β3 adrenergic receptor agonists;     -   (l) Heal bile acid transporter inhibitors;     -   (m) Agents intended for use in inflammatory conditions such as         aspirin, non-steroidal, anti-inflammatory drugs,         glucocorticoids, azulfidine and cyclo-oxygenase 2 selective         inhibitors;     -   (n) Glucagon receptor antagonists;     -   (o) GLP-1;     -   (p) GIP-1;     -   (q) GLP-1 analogs, such as exendins, for example exenitide, and     -   (r) Hydroxysterol dehydrogenase-1 (HSD-1) inhibitors.

The above combinations include combinations of a compound of the present invention or a pharmaceutically acceptable salt or solvate not only with one other active compound but also with two or more active compounds. Non limiting examples include combinations of compounds having Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors and anti-obesity compounds.

In the above-described embodiment combinations of the present invention, the compound of Formula I, a pharmaceutically acceptable salt or solvate thereof and other therapeutic active agents may be administered in terms of dosage forms either separately or in conjunction with each other, and in terms of their time of administration, either serially or simultaneously. Thus, the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).

The invention also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. As indicated above, the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.

Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient.

The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament. Preferably, the medicament is used for the treatment and/or prevention of type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).

Preferred diseases are type II diabetes, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.

In a particular preferred embodiment the disease are type II diabetes and a lipid disorder such as dyslipidemia.

According to a further feature of the present invention there is provided the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for modulating GPR43 receptor activity, in a patient, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

Preferably, the patient is a warm-blooded animal, more preferably a human.

As set forth above, the compounds of the invention, their pharmaceutically acceptable salts, solvates and prodrugs may be used in monotherapy or in combination therapy. Thus, according to one embodiment, the invention provides the use of a compound of the invention for the manufacture of a medicament for at least one of the purposes described above, wherein said medicament is administered to a patient in need thereof, preferably a warm-blooded animal, and even more preferably a human, in combination with at least one additional therapeutic agent and/or active ingredient. The benefits and advantages of such a multiple drug regimen, possible administration regimens as well as suitable additional therapeutic agents and/or active ingredients are those described above.

Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms which may be solid, semi-solid or liquid, depending on the manner of administration as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.

The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 0.05 and 1000 mg, and usually between 1 and 500 mg, of at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.

Usually, depending on the condition to be prevented or treated and the route of administration, the active compound of the invention will usually be administered between 0.01 to 100 mg per kilogram, more often between 0.1 and 50 mg, such as between 1 and 25 mg, for example about 0.5, 1, 5, 10, 15, 20 or 25 mg, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.

[Definitions]

The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

Where groups may be substituted, such groups may be substituted with one or more substituents, and preferably with one, two or three substituents.

Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, cyano, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.

As used herein the terms such as “alkyl, aryl, or cycloalkyl, each being optionally substituted with . . . ” or “alkyl, aryl, or cycloalkyl, optionally substituted with . . . ” encompasses “alkyl optionally substituted with . . . ”, “aryl optionally substituted with . . . ” and “cycloalkyl optionally substituted with . . . ”.

The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro.

The term “alkyl” by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C₁H_(2n+1) wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. C_(x-y)-alkyl and Cx-Cy-alkyl refer to alkyl groups which comprise from x to y carbon atoms.

Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and tert-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and tert-butyl.

When the suffix “ene” (“alkylene”) is used in conjunction with an alkyl group, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. The term “alkylene” includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethylethylene.

The term “alkenyl” as used herein refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.

The term “alkynyl” as used herein refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups. Non limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers—and the like. The terms “alkenylene” and “alkynylene” respectively mean an alkenyl group or an alkinyl group as defined above having two single bonds as points of attachment to other groups.

The term “haloalkyl” alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.

The term “cycloalkyl” as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.

When the suffix “ene” is used in conjunction with a cyclic group, this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups.

Therefore, “cycloalkylene” herein refers to a saturated homocyclic hydrocarbyl biradical of Formula C_(n)H_(2n−2). Suitable cycloalkylene groups are C₃₋₆ cycloalkylene group, preferably a C₃₋₅ cycloalkylene (i.e. 1,2cyclopropylene, 1,1-cyclopropylene, 1,1-cyclobutylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,3-cyclopentylene, or 1,1-cyclopentylene), more preferably a C₃₋₄ cycloalkylene (i.e. 1,3-cyclopropylene, 1,1-cyclopropylene, 1,1-cyclobutylene, 1,2-cyclobutylene).

Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as “heterocycloalkyl” or “heterocyclyl”.

The terms “heterocyclyl”, “heterocycloalkyl” or “heterocyclo” as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone). The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more Spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thio morpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl.

The ring atoms of heterocyclyl and heterocyclylene moieties are numbered based on scheme below

The term “aryl” as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1-2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.

The term “arylene” as used herein is intended to include divalent carbocyclic aromatic ring systems such as phenylene, biphenylylene, naphthylene, indenylene, pentalenylene, azulenylene and the like. Arylene is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthylene, 1,4-dihydronaphthylene and the like.

The term “arylalkyl” or “aralkyl” refers to a linear or branched alkyl group where one carbon is attached to an aryl ring. Non limiting examples of aralkyl comprise benzyl, phenethyl, (naphtalen-1-yl) or (naphtalen-2-yl)methyl. When an aralkyl group is substituted, the substituent(s) is/are attached either on the alkyl group or on the aryl ring. A “x-membered aralkyl” refers to a linear or branched alkyl group where one carbon is attached to a x-membered aryl ring. Where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.

The term “heteroaryl” as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

The term “heteroarylene” as used herein means divalent carbocyclic aromatic ring systems including pyridinylene and the like.

The ring atoms of heteroaryl or heteroarylene moieties are numbered on scheme below:

The term “biaryl” as used herein designates two aryl moieties as defined herein linked via a single bond. Non-limiting examples of such biaryl moieties include biphenyl.

The term “heterobiaryl” as used herein designates two heteroaryl moieties as defined herein or a heteroaryl moiety and an aryl moiety as defined herein linked via a single bond. Non-limiting examples of such heterobiaryl moieties include pyridinylphenyl which is meant to include (2-pyridinyl)phenyl, (3-pyridinyl)phenyl and (4-pyridinyl)phenyl, bipyridinyl.

The term “alkylamino” as used herein means an amino group substituted with one or two alkyl groups. This includes monoalkylamino and dialkylamino groups.

The term “carbamoyl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The term “carbamimidoyl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The term “carbamimidoyl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The compounds of Formula I and subformulae thereof contain at least one asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994), incorporated by reference with regard to stereochemistry.

The bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line (

), a zigzag line (

), a solid wedge (

) or a dotted wedge (

), a solid bar (

) or a dotted bar (

). The use of a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. The use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included.

The compounds of the invention may also contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds from asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended. In those compounds, the use of solid or dotted bars is meant to indicate relative stereochemistry. As an example,

The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. Preferred, pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.

When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of these methods:

(i) by reacting the compound of Formula I with the desired acid;

(ii) by reacting the compound of Formula I with the desired base;

(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or

(iv) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

All these reactions are typically carried out in solution. The salt, may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

The term “solvate” is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.

All references to compounds of formula I include references to salts, solvates, multi-component complexes and liquid crystals thereof.

The compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labeled compounds of formula I.

In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.

The invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.

The term “prodrug” as used herein means the pharmacologically acceptable derivatives of compounds of formula I such as esters whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters as well as compounds of formula I in which Z is a substituent selected from the table 2 below.

TABLE 2 Z Q —C(O)SQ Alkyl or aryl —C(O)NQ¹Q² Q¹ and Q² independently selected from: H, alkyl, aryl, OH or NH₂ —C(O)OCHQ¹O(O)CQ² Q¹ = H or phenyl Q² = alkyl or aryl —C(O)OCHQCl H or aryl —C(OQ)₃ Alkyl —C(O)OC(O)OQ Alkyl or aryl —C(O)CH₂Q SMe, SOMe, SO₂Me

The term “predrug”, as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.

The term “patient” refers to a warm-blooded animal, more preferably a human, who/which is awaiting or receiving medical care or is or will be the object of a medical procedure.

The term “human” refers to subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).

The terms “treat”, “treating” and “treatment, as used herein, are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention”, as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.

The term “therapeutically effective amount” (or more simply an “effective amount”) as used herein means the amount of active agent or active ingredient (e. g. GPR43 agonist or partial agonist) which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.

The term “administration”, or a variant thereof (e.g.,“administering”), means providing the active agent or active ingredient (e. g. a GPR43 agonist or partial agonist), alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.

By “pharmaceutically acceptable” is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.

The term “agonist” as used herein means a ligand that activates an intracellular response when it binds to a receptor. An agonist according to the invention may promote internalization of a cell surface receptor such that the cell surface concentration of a receptor is decreased or remove.

The term “partial agonist” as used herein means an agonist which is unable to induce maximal activation of a receptor, regardless of the amount of compound applied on the receptor.

The term “pharmaceutical vehicle” as used herein means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.

The term “lipid disorder” as used herein means any plasma lipid disorder including but not limited to dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia and hypertriglyceridemia.

The present invention will be better understood with reference to the following examples. These examples are intended to representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.

Chemistry Examples

All temperatures are expressed in ° C. and all reactions were carried out at room temperature (RT) unless otherwise stated.

Analytical thin layer chromatography (TLC) was used to monitor reactions, establish flash chromatography conditions and verify purity of intermediates or final products. TLC plates used were Merck TLC aluminium sheet silica gel 60 F₂₅₄. TLC plates were revealed using ultraviolet irradiation (wavelength=254 nm) at RT or bromocresol green spray reagent at 0.1% in propan-2-ol or KMnO₄ revelator (KMnO₄, Na₂CO₃, NaOH, H₂O) upon heating at 160° C.

HPLC-MS spectra were obtained on Agilent LCMS using Electrospray ionization (ESI). The Agilent instrument includes an Autosampler 1200, a binary pump 1100, a 5 wave length detector 1100 and a 6100 Single Quad. The column used was an XBridge C18.

Eluent was a mixture of solution A (0.1% TFA in H₂O) and solution B (0.1% TFA in ACN). Gradients used are as follows: gradient A (intermediates characterization): held the initial conditions of 5% solution B for 1 min, increased linearly to 95% solution B in 4 min, held at 95% during 1 min, returned to initial conditions in 0.5 min and maintained for 1 min; gradient B (examples characterization): held the initial conditions of 5% solution B for 1 min, increased linearly to 60% in 10 min, increased linearly to 95% in 0.5 min, held at 95% during 3 min, returned to initial conditions in 0.5 min and maintained for 1 min.

Determination of enantiomeric excess was performed on an Agilent 1100 (binary pump and 5 wavelengths detector) with manual or automatic (Autosampler 1100) injection. Columns used were CHIRALPAK IA CHIRALPAK TB or CHIRALPAK IC in isocratic mode. Mixtures of eluents were selected depending on the separation obtained of enantiomers or diastereosiomers. Usual mixtures were:

Hexane and Ethanol (0.1% TFA)

Hexane and Propanol (0.1% TFA)

Hexane and Ethyl acetate (0.1% TFA)

Hexane and Dichloromethane (0.1% TFA)

Hexane and tert-butyl methyl ether (0.1% TFA)

Preparative HPLC purifications were carried out on Fractionlynx instrument, from Waters. This instrument consists of a Fraction Collector, a 2767 Sample Manager, a pump control a module II, a 515 HPLC Pump, a 2525 Binary Gradient Module, a Switching Valve, a 2996 Photodiode Array Detector and a Micromass ZQ. The column used was a Waters Sunfire C18 Eluent was a mixture of solution A (0.1% TFA in H₂O) and solution B (0.1% TFA in ACN). The gradient was adapted depending on impurities present in samples, to allow sufficient separation between impurities and target compound.

Chiral preparative HPLC purification were performed on an Agilent 1100 instrument (binary pump and 5 wavelengths detector) with manual injection using a CHIRALPAK IA or a CHIRALPAK IB column in isocratic mode. Mixtures of eluents were selected depending on the separation of enantiomers or diastereosiomers obtained with the analytical method. Usual mixtures were the same as those used for the determination of ee.

¹H and ¹³C NMR spectra were recorded on a Bruker ARX 300 MHz. Chemical shifts are expressed in parts per million, (ppm, 6 units). Coupling constants are expressed in Hertz units (Hz). Splitting patterns describe apparent multiplicities and are described as s (singlet), d (doublet), t (triplet), q (quintet), m (multiplet), or br (broad).

Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, VWR Int., Sopachem or Polymer labs and the following abbreviations are used:

-   ACN or MeCN: Acetonitrile, -   DCM: Dichloromethane, -   DCE: 1,2-Dichloroethane, -   EtOAc or AcOEt: Ethyl acetate, -   EtOH: Ethanol, -   MeOH: Methanol, -   IPA: isopropanol, -   PE: Petroleum ether, -   NMP: N-methylpyrrolidinone, -   RT: Room temperature, -   DIEA: N,N-diisopropylethylamine, -   HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tretramethyluronium     hexafluorophosphate, -   HOBt: 1-hydroxybenzotriazole or 1-hydroxybenzotriazole hydrate, -   DMAP: N,N-Dimethylaminopyridine -   Y: Yield, -   g: Grams, -   mg: Milligrams, -   L: Liters, -   mL: Milliliters, -   μL: Microliters, -   mol: Moles, -   mmol: Millimoles, -   h: Hours, -   min or mn: Minutes, -   TLC: Thin layer chromatography, -   MW: Molecular weight, -   eq: Equivalent, -   THF: Tetrahydrofuran, -   TFA: Trifluoroacetic acid, -   Ac: Acetyl, -   ee: Enantiomeric excess, -   tBu: tert-Butyl -   P: UV purity at 254 nm determined by HPLC-MS, -   rt: Retention time, -   BuLi: butyllithium, -   CDI: carbonyldiimidazole, -   TBDPS: tert-butyl-diphenylsilyl, -   Boc₂O: di-tert-butyldicarbonate, -   TBAF: tetrabutylammonium fluoride, -   S-Phos: 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, -   RM: reaction mixture, -   Nu: Nucleophile, -   DMF: N,N-dimethylformamide, -   TMS: trimethylsilyl.     General Synthetic Schemes

A general method for the synthesis of most compounds of the invention is outlined in scheme 1.

Pyrrolidine methyl acetate intermediate 1.1 was acylated with acyl chlorides or carboxylic acids intermediates 1.2 using standard amide coupling procedures to give epimeric mixture compound 1.3.

In some cases epimers 1.3a and 1.3b were separated by chromatography (flash chromatography or preparative HPLC); subsequent saponification of intermediates 1.3a and 1.3b with lithium hydroxide afforded the desired carboxylic acid products 1.4 and 1.5 respectively.

Otherwise intermediate 1.3 was saponified with lithium hydroxide to give epimeric mixture 1.6 which was purified by chromatography (flash chromatography or preparative HPLC) to give desired carboxylic acid products 1.4 and 1.5.

Pyrrolidine ester intermediates 1.1 were synthesized from aryl or alkyl Grignard or aryl-lithium reagents as shown in scheme 2.

Addition of aryl or alkyl Grignard or aryl-lithium 2.1 to N-Boc-L-pyroglutamic acid methyl ester 2.2 provided intermediate 2.3, as described by Colandrea et al. in Bioorg. & Med. Chem. Lett. 2006, 16, 2905-2908 and Ying-zi Xu et al. in J. Org. Chem. 1999, 64, 4069-4078. One pot Boc deprotection and cyclic imine formation under acidic conditions afforded cyclic imine intermediate 2.4 which could be reduced either by hydrogenation or by borohydride reagent to give the pyrrolidine ester intermediate 1.1. In some cases epimers 1.1a and 1.1b were separated by flash chromatography.

Aryl or alkyl Grignard and aryl-lithium reagents 2.1 were prepared using the methodologies shown in scheme

Aryl or alkyl Grignard reagents 2.1a were prepared from aryl halides either by method 1 (isopropyl megnasium chloride/lithium chloride) or by method 2 (magnesium) and aryl-lithium reagents 2.1b were synthesized by method 3 (n-butyllithium).

N-Boc-L-pyroglutamic acid methyl ester 2.2 was synthesized using the methodology shown in scheme 4

L-pyroglutamic acid 4.1 was converted to the methyl ester 4.2 which upon Boc protection with di-tert-butyl dicarbonate afforded intermediate 2.2.

Biaryl and heterobiaryl carboxylic acid intermediates 1.2a were synthesized using one of the three routes (a, b or c) shown in scheme 5.

Suzuki coupling between 5.1 and 5.2 provided biaryl ester intermediate 5.3, subsequent saponification with lithium hydroxide afforded biaryl carboxylic acid intermediate 1.2a.

Aralkyloxyaryl carboxylic acid intermediates 1.2 were synthesized using the methodology shown in scheme 6 for benzyloxybenzoic acid intermediates 1.2b.

Methyl 3,5-dihydroxybenzoate 6.1 was methylated with dimehylsulfate to give intermediate 6.2. Benzylation with benzyl halide reagent 6.3 provided ester intermediate 6.4 which upon subsequent saponification with lithium hydroxide afforded benzyloxybenzoic acid intermediates 1.2b Additional Synthetic Schemes

Synthesis of compound n^(o) 24 is depicted in scheme 7.

Synthesis of methyl substituted pyrrolidinone intermediates 2.2 is depicted in scheme 8.

Dipolar cycloaddition methodology is exemplified with the synthesis of compound n^(o) 217 and is depicted in scheme 9.

Synthesis of compound n^(o) 268 is depicted in scheme 10.

Synthesis of intermediate 3-methoxy-4-(4-methylpiperidin-1-yl)benzoic acid used in the preparation of compound n^(o) 261 is depicted in scheme 11.

The synthesis of compound n^(o) 393 is depicted in scheme 12.

The synthesis of compound n^(o) 369 is depicted in scheme 13.

Synthesis of compound n^(o) 279 is depicted in scheme

General Methods

General Method A: Synthesis of Pyrrolidine Ester Intermediates 1.1

General method A is exemplified with the synthesis of intermediate 1a (2S,5R)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate, intermediate 1b (2S,5S)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate and intermediate 1f (2S,5R)-methyl 5-(pyridin-2-yl)pyrrolidine-2-carboxylate from 2-bromopyridine (route 3, conditions E)

Step 1: Synthesis of (2-chlorophenyl)magnesium chloride: Route 1

To a 2M solution of isopropylmagnesium chloride in anhydrous THF (5.76 mmol) was added lithium chloride (5.76 mmol) in distilled THF in a Schlenk tube under Ar atmosphere at RT. The reaction mixture was cooled to −15° C. and 1-bromo-2-chlorobenzene (5.35 mmol) was added and the RM was stirred at −15° C. for another 3 h. This crude solution of (2-chlorophenyl)magnesium chloride was cooled to −40° C. and used as such in step 2.

Step 2: Synthesis of (S)-methyl 2-((tert-butoxycarbonyl)amino)-5-(2-chlorophenyl)-5-oxopentanoate

To the crude solution of (2-chlorophenyl)magnesium chloride obtained in step 1 was added at −40° C. under Ar a solution of (S)-1-tert-butyl 2-methyl 5-oxopyrrolidine-1,2-dicarboxylate (4.11 mmol) in distilled THF (4 mL). The reaction mixture was stirred at 40° C. for 2 h and then quenched with 10 mL of a saturated aqueous solution of ammonium chloride. The mixture was extracted three times with AcOEt, combined organics were dried over anhydrous MgSO₄ and concentrated in vacuo. Crude was purified by flash chromatography (eluent: cyclohexane/AcOEt) to yield title compound. Y: 425 mg (29%), P: >95%, rt=4.24 min, (M+H)⁺=256.

Step 3: synthesis of (S)-methyl 5-(2-chlorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate

TFA (2 mL) was added to a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-5-(2-chlorophenyl)-5-oxopentanoate (1.08 mmol) in DCM (2 mL) and the reaction mixture was stirred at RT for 2 h. The RM was evaporated to dryness to yield title compound. Y: 574 mg (56%), P: >95%, rt=2.85 min, (M+H)⁻=238.

Step 4 Reaction conditions C: synthesis of intermediate 1a (2S,5R)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate and intermediate 1b (2S,5S)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate

Sodium triacetoxyborohydride (0.091 mol) was added portionwise to a stirred solution of (S)-methyl 5-(2-chlorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (0.076 mol) in 1,2-dichloroethane (200 mL) at RT under a nitrogen atmosphere. TFA (0.76 mol) was added and the reaction mixture was stirred at RT for 1.5 h. LCMS showed starting material still remaining so further TFA (˜10 mL) was added (to give pH 3-4) and stirring continued for a further 1.5 h. All starting material was consumed, water (30 mL) was added followed by saturated aqueous NaHCO₃ (˜400 mL) until neutral pH. The separated aqueous layer was extracted with DCM (2×300 ml) and the combined organics dried over anhydrous MgSO₄ and evaporated in vacuo to give a yellow oil (17.5 g). Crude was purified by column chromatography (eluent: PE/EtOAc) to give, as colourless oils, intermediate 1a: Y: 12 g (66%), P: >95%, rt=2.73 min, (M+H)⁺=240 and intermediate 1b Y: 3 g (16%), P: >95%, (M+H)⁺=240.

Reaction conditions D: synthesis of intermediate (2S)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate

Sodium cyanoborohydride (2.9 mmol) was added to a solution of (S)-methyl 5-(2-chlorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (2.42 mmol) in anhydrous MeOH (20 mL) and the reaction mixture was stirred at RT for 1 h. The RM was quenched with water and extracted with DCM. Combined organics were dried over anhydrous MgSO₄ and concentrated in vacuo to yield title compound. Y: 338 mg (59%), P: >95%, rt=2.73 min, (M+H)⁺=240.

Reaction conditions E: synthesis of intermediate 1f: (2S,5R)-methyl 5-(pyridin-2-yl)pyrrolidine-2-carboxylate from 2-bromopyridine (route 3)

In a 10 mL round bottomed flask was dissolved (S)-methyl 5-(pyridin-2-yl)-3,4-dihydro-2H-pyrrole-2-carboxylate (0.208 mmol) in IPA (550 μL) to give a brown solution. Palladium on carbon (3.95 μmol) (10% w/w) was added, and reaction was stirred under H₂ atmosphere.

Reaction mixture was stirred overnight at RT. The mixture was filtered through celite and concentrated under reduced pressure to give intermediate 1f in a quantitative yield. Y: 12 g (66%), P: >95%, rt=2.34 min, (M+H)⁺=207.

The following intermediates were synthesized from ad-hoc reagents using general method A:

intermediate 1c: (2S,5R)-methyl 5-(3-chloropyridin-2-yl)pyrrolidine-2-carboxylate from 2-bromo-3-chloropyridine (route 3, conditions C);

intermediate 1e: (2S)-methyl 5-([1,1′-biphenyl]-3-yl)pyrrolidine-2-carboxylate from biphenyl-3-ylmagnesium bromide (conditions C);

intermediate 1g: (2S)-methyl 5-(2-fluorophenyl)pyrrolidine-2-carboxylate from 1-bromo-2-fluorobenzene (route 1, conditions C), rt=2.5 min (gradient A);

intermediate 1i: (2S)-methyl 5-(2-methoxyphenyl)pyrrolidine-2-carboxylate 1-bromo-2-methoxybenzene (route 1, conditions D);

intermediate 1j: (2R)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate from 1-bromo-2-chlorobenzene (route 1, conditions D);

intermediate 1k: (2S)-methyl 5-(4-chlorophenyl)pyrrolidine-2-carboxylate from 4-chlorophenylmagnesium bromide (conditions C);

intermediate 1l: (2S)-methyl 5-([1,1′-biphenyl]-4-yl)pyrrolidine-2-carboxylate from [1,1′-biphenyl]-4-ylmagnesium bromide (conditions C);

intermediate 1m: (2S)-methyl 5-(2-chlorobenzyl)pyrrolidine-2-carboxylate from 2-chlorobenzylmagnesium chloride (conditions C);

intermediate 1n: (2S)-methyl 5-cyclohexylpyrrolidine-2-carboxylate from cyclohexylmagnesium chloride (conditions C);

intermediate 1o: (2S)-methyl 5-([1,1′-biphenyl]-2-yl)pyrrolidine-2-carboxylate from [1,1′-biphenyl]-2-ylmagnesium bromide (conditions C);

intermediate 1p: (2S,5R)-methyl 5-(2-chlorophenyl)-4,4-dimethylpyrrolidine-2-carboxylate (conditions C), starting from (S)-1-tert-butyl 2-methyl 4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate obtained using the synthetic route described in scheme 8;

intermediate 1q: (2S,5R)-methyl 5-(2-chlorophenyl)-4-methylpyrrolidine-2-carboxylate (conditions C), starting from (S)-1-tert-butyl 2-methyl-4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate;

intermediate 1r: (2S,5R)-methyl 5-(pyridin-3-yl)pyrrolidine-2-carboxylate;

intermediate 1s: (2S,5R)-methyl 5-(o-tolyl)pyrrolidine-2-carboxylate;

intermediate 1t: (2S,5R)-methyl 5-phenylpyrrolidine-2-carboxylate (condition E);

intermediate 1u: (2S,5R)-methyl 5-(3-chlorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C);

intermediate 1v: (2S,5R)-methyl 5-(4-chlorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C);

intermediate 1w: (2S,5R)-5-(3-fluorophenyl)pyrrolidine-2-carboxylic acid (route 1, conditions E);

intermediate 1x: (2S,5R)-methyl 5-(4-fluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions E);

intermediate 1y: (2S,5R)-methyl 5-cyclohexylpyrrolidine-2-carboxylate was synthesized by hydrogenation of intermediate 1t using PtO₂ in MeOH,

intermediate 1z: (2R,5R)-methyl 5-(2-fluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C);

intermediate 1a1: (2S,5S)-methyl 5-(2-fluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C);

intermediate 1b1: (2R,5S)-methyl 5-(2-fluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C);

intermediate 1c1: (2S,5R)-methyl 5-(2,6-difluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions E);

intermediate 1d1: (2S,5R)-methyl 5-(2,4-difluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions E);

intermediate 1e1: (2S,5R)-methyl 5-(2,4-dichlorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C);

intermediate 1f1: (2S,5R)-methyl 5-isobutylpyrrolidine-2-carboxylate (route 2, conditions E);

intermediate 1g1: (2S,5R)-methyl 5-isopropylpyrrolidine-2-carboxylate (route 1, conditions E);

intermediate 1h1: (2S,5R)-methyl 5-cyclopentylpyrrolidine-2-carboxylate (conditions E);

intermediate 1i1: (2S,5R)-methyl 5-(2-bromophenyl)pyrrolidine-2-carboxylate (route 1, conditions C);

intermediate 1j1: (2S,5S)-methyl 5-isopentylpyrrolidine-2-carboxylate (route 2, conditions E);

intermediate 1k1: (2S,5R)-methyl 5-(2,4-difluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions E);

intermediate 1l1: (2S,5R)-methyl 5-(3,5-difluorophenyl)pyrrolidine-2-icarboxylate (route 1, conditions C);

intermediate 1m1: (2S,5R)-methyl 5-(3,4-difluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C);

intermediate 1n1: (2S,5R)-methyl 5-(2,3-difluorophenyl)pyrrolidine-2carboxylate (route 1, conditions C), rt=2.6 min (gradient A);

intermediate 1o1: (2S,5R)-methyl 5-(2,5-difluorophenyl)pyrrolidine-2-carboxylate (route 1, conditions C);

intermediate 1p1: (2S,5R)-methyl 5-(4-cyanophenyl)pyrrolidine-2-carboxylate. (route 1, conditions C).

General Method B: Synthesis of Aryloxyaryl Carboxylic Acid Intermediates 1.2b

General method B is exemplified with the synthesis of intermediate 2a 3-(benzyloxy)-5-methoxybenzoic acid

Step 1: Synthesis of methyl 3-hydroxy-5-methoxybenzoate

To a solution of methyl 3,5-dihydroxybenzoate (29.76 mmol) in anhydrous acetone (40 mL) was added dimethylsulfate (29.69 mmol), tetrabutylammonium iodide (2.97 mmol) and potassium carbonate (59.42 mmol). The reaction mixture was stirred at RT overnight. The RM was diluted with water and extracted with AcOEt. Combined organics were dried over anhydrous MgSO₄ and concentrated in vacuo. Crude was purified by flash chromatography (eluent: PE/AcOEt) to yield title compound. Y: 1.7 g (31%), P: >95%, rt=3.75 min, (M+H)⁺=183.

Step 2: synthesis of methyl 3-(benzyloxy)-5-methoxybenzoate

To a solution of methyl 3-hydroxy-5-methoxybenzoate (0.55 mmol) in anhydrous acetone (2 mL) was added benzyl bromide (0.55 mmol), potassium carbonate (0.66 mmol) and sodium iodide (0.055 mmol). The reaction mixture was stirred at 55° C. for 5 h. The RM was diluted with AcOEt and a 1M aqueous solution of sodium hydroxide. The organic layer was separated, dried over anhydrous MgSO₄ and concentrated in vacuo. Crude was purified by flash chromatography (eluent: PE/AcOEt) to yield title compound. Y: 104 mg (69%), P: >95%, rt=4.53 min, (M+H)⁺=273.

Step 3: synthesis of intermediate 2a 3-(benzyloxy)-5-methoxybenzoic acid

To a solution of methyl 3-(benzyloxy)-5-methoxybenzoate (0.38 mmol) in THF (1 mL) was added a solution of lithium hydroxide (1.53 mmol) in water (1 mL). The reaction mixture was stirred at RT overnight. The RM was quenched with a 1M HCl aqueous solution and extracted three times with DCM. Combined organics were dried over anhydrous MgSO₄ and concentrated in vacuo to yield title compound. Y: 92 mg (94%), P: >95%, rt=3.95 mn, (M+H)⁺=259.

The following intermediates were synthesized from ad-hoc reagents using general method B:

intermediate 2b: 3((4-chlorobenzyl)oxy)-5-methoxybenzoic acid,

intermediate 2c: 3-methoxy-5-phenethoxybenzoic acid,

intermediate 2d: 3-(3,3-diphenylpropoxy)-5-methoxybenzoic acid,

intermediate 2e: 3-methoxy-5-((4-(methylsulfonyl)benzyl)oxy)benzoic acid,

intermediate 2f: 3-methoxy-5-(2-methoxyethoxy)benzoic acid,

intermediate 2g: 3-(3,5-dimethylisoxazol-4-yl)methoxy)-5-methoxybenzoic acid,

General Method C: Synthesis of Most Compounds of the Invention

General method C is exemplified with the synthesis of Example 1: compound n^(o) 1: (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid

Step 1: Synthesis of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate

Conditions A:

In a 100 mL round bottom flask, under argon, was dissolved 2′-methoxybiphenyl-4-carboxylic acid (15.714 g, 68.8 mmol) in DCM (138 mL). A white suspension was obtained to which were successively added thionyl chloride (7.49 mL, 103 mmol) and DMF (0.107 mL, 1.377 mmol). Reaction mixture was heated at reflux (40° C.) 3 hours. The solution was allowed to reach spontaneously RT (yellow-orange solution). RM was concentrated under reduced pressure. Removal of the excess of thionyl chloride was done by two co-evaporation cycles with DCM. The resulting brown residue was dried under vacuum to afford 17 g of a brown solid. Crude product was used without further purification in the next step.

In a 500 mL, round bottom flask were introduced under argon methyl (2S,5R)-5-(2-chlorophenyl)pyrrolidine-2-carboxylate (15 g, 62.6 mmol), DCM (62.4 mL) and Et₃N (9.59 mL, 68.8 mmol). To this solution cooled to 0° C., was added dropwise (via an addition funnel) a solution of 2′-methoxybiphenyl-4-carbonyl chloride (16.98 g, 68.8 mmol) in DCM (83 mL) (dark brown solution). The RM was stirred from 0° C. to RT overnight. The RM was transferred to a separation funnel and washed with 25 mL of HCl 6M diluted with 75 mL water. The organic layer was dried under stirring with MgSO₄ in the presence of 0.3 g of Norit AS, filtered and concentrated to afford 34 g of a light brown foaming oily residue. Purification by column chromatography (eluent: EtOAc/PE: 1/2) yielded desired product as a beige solid. Y: 25.4 g (90%), P>95%.

Conditions B: To a solution of 2′-methoxybiphenyl-4-carboxylic acid 2b (1.1 mmol) in anhydrous ACN (2 mL) was added HATU (1.1 mmol). After 5 min was added (2S,5R)-methyl 5-(2-chlorophenyl)pyrrolidine-2-carboxylate 1a (1 mmol) and DIEA (1.2 mmol). Reaction mixture was stirred at RT for 4 days. Reaction mixture was diluted with AcOEt and washed with saturated aqueous solution of NaHCO₃ and with water. The organic phase was dried over MgSO₄ and evaporated. Crude was purified by flash chromatography (eluent: cyclohexane/AcOEt) to yield title compound. Y: 300 mg (67%), P>95%, rt=4.85 min (M+H)⁺=451.

Step 2: synthesis of Example 1: compound n^(o) 1: (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid

To a solution of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate (0.67 mmol) in THF (5 mL) was added a solution of lithium hydroxide (2.67 mmol) in water (5 mL). The reaction mixture was stirred at RT overnight. The RM was quenched with a 1M HCl aqueous solution and extracted twice with AcOEt. Combined organics were dried over anhydrous MgSO₄ and concentrated in vacuo to yield title compound as a colorless solid. Y: 250 mg (86%), P: >95%, rt=6.05 min, (M+H)⁺=436.

General Method D: Synthesis of Biaryl Carboxylic Acid Intermediates 1.2a

Three routes (a, b and c) were used in the preparation of biaryl or heterobiaryl intermediates.

Route a is exemplified with the synthesis of intermediate 2h 2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid Step 1: Synthesis of methyl 2′-methoxy-[1,1′-biphenyl]-4-carboxylate

A mixture of methyl-4-iodobenzoate (86.2 g, 0.33 mol) and 2-methoxyphenyl boronic acid (50.0 g, 0.33 mol) in toluene (975 mL) and EtOH (525 mL) was degassed with nitrogen bubbling for 30 minutes. Pd(PPh₃)₄ (19.0 g, 16.5 mmol) and 4M aqueous Na₂CO₃ (271.5 mL, 1.09 mol) were added and the mixture stirred at 100° C. under a nitrogen atmosphere overnight. After cooling to room temperature, EtOAc (1.5 L) and water (1.5 L) were added, and the separated organic layer was dried (Na₂SO₄) and evaporated in vacuo to leave a brown oily solid (107 g). The residue was purified by column chromatography using an increasing gradient from 5-50% EtOAc/petrol to give title product as a yellow solid. Y: 51 g (64%), P>80%.

Step 2: Synthesis of intermediate 2h 2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid

LiOH.H₂O (89 g, 2.1 mol) was added to a stirred suspension of methyl 2′-methoxy-[1,1′-biphenyl]-4-carboxylate (51 g, 0.21 mol) in a mixture of THF (500 mL) and H₂O (1 L). Further amounts of THF (˜500 mL) and H₂O (˜1 L) were added to dissolve the majority of the solids. After stirring overnight at room temperature, more solids had precipitated and starting material still remained. The mixture was heated to 50° C. for 4 hours, after which time all solids had dissolved and no starting material remained. After cooling to room temperature, saturated aqueous citric acid was added until pH=6-7, which produced a white precipitate. THF was removed by evaporation in vacuo and the resulting suspension filtered. The solid was washed with water several times and dried at 50° C. overnight to give intermediate 2h as an off-white solid. Y: 43 g (90%), P>90%.

Route b is exemplified with the synthesis of intermediate 2s2 4-(2-methoxypyrimidin-4-yl)benzoic acid Step 1: Synthesis of methyl 4-(2-methoxypyrimidin-4-yl)benzoate

In an oven dried glass tube, were introduced under argon 4-methoxycarbonylphenylboronic acid (381 mg, 2.116 mmol) and 4-bromo-2-methoxypyrimidine (200 mg, 1.058 mmol). Three vacuum/Argon cycles were performed and toluene (5 mL) was added, followed by a 2M aqueous solution of K₂CO₃ (0.106 mmol). The resulting mixture was degassed (argon bubbling into the solution for 5-10 minutes).

Tetrakis(triphenylphosphine)palladium(0) (0.1 mmol) was then added and the mixture was heated to 95° C. overnight. The mixture was cooled down to room temperature and then diluted with EtOAc and washed with brine. The aqueous layer was further extracted with EtOAc and the combined organic layers were dried and concentrated. The residue was purified on silica gel (cyclohexane/EtOAc), furnishing 243 mg of desired product as a pale yellow solid (94% yield).

Step 2: Synthesis of intermediate 2s2 4-(2-methoxypyrimidin-4-yl)benzoic acid

The same conditions as in step 2 of route a were used.

The following intermediates were synthesized from ad-hoc reagents using general method D route b:

intermediate 2i: 2′,5′-dichloro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2j: 4-(pyrimidin-5-yl)benzoic acid;

intermediate 2k: 4-(furan-3-yl)benzoic acid;

intermediate 2l: 4-(6-methoxypyridin-3-yl)benzoic acid,

intermediate 2m: 4-(3-fluoropyridin-4-yl)benzoic acid;

intermediate 2n: 4-(pyridin-3-yl)benzoic acid;

intermediate 2o: 4-(6-(dimethylamino)pyridin-3-yl)benzoic acid;

intermediate 2p: 4-(pyridin-4-yl)benzoic acid;

intermediate 2q: 4-(6-methylpyridin-3-yl)benzoic acid;

intermediate 2r: 4-(2-methoxypyridin-3-yl)benzoic acid, rt=3.4 min (gradient A);

intermediate 2s: 4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2t: 4′-cyano-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2u: 4-(4-methoxypyridin-3-yl)benzoic acid;

intermediate 2v: 4′-chloro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2w: 3′-chloro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2x: 2′-chloro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2y: 4′-(methylsulfonamido)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2z: 3′-(methylsulfonamido)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2a1: 2′-(methylsulfonamido)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2b1: 4-(naphthalen-2-yl)benzoic acid;

intermediate 2c1: 3′,5′-difluoro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2d1: 2′-hydroxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2e1: 2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2f1: 4-(3-fluoropyridin-4-yl)benzoic acid;

intermediate 2g1: 4-(6-chloropyridin-3-yl)benzoic acid;

intermediate 2h1: 4-(6-fluoropyridin-3-yl)benzoic acid;

intermediate 2i1: 5-methoxy-6-phenylnicotinic acid;

intermediate 2j1: 4-(3-methoxypyridin-4-yl)benzoic acid;

intermediate 2k1: 2-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2l1: 4-(6-chloropyridin-3-yl)benzoic acid;

intermediate 2m1: 4-(6-fluoropyridin-3-yl)benzoic acid;

intermediate 2n1: 4-(thiophen-3-yl)benzoic acid;

intermediate 2o1: 4-cyclohexylbenzoic acid;

intermediate 2p1: 2′-(methylsulfonyl)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2q1: 4-(pyrimidin-2-yl)benzoic acid;

intermediate 2r1: 4-(4,6-dimethoxypyrimidin-2-yl)benzoic acid;

intermediate 2s1: 4-(2,4-dimethoxypyrimidin-5-yl)benzoic acid, rt=3.4 min (gradient A);

intermediate 2t1: 4-(2-methoxypyrimidin-5-yl)benzoic acid;

intermediate 2u1: 4-(pyridin-2-yl)benzoic acid;

intermediate 2v1: 2′-cyano-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2w1: 2′,6′-dimethoxy-[1,1′-biphenyl]-4-carboxylic acid,

intermediate 2x1: 2′,4′-dichloro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2y1: 2′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2z1: 2,2′-dimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2a2: 4′-chloro-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2b2: 4-(4-methoxypyrimidin-5-yl)benzoic acid;

intermediate 2c2: 4-(3-fluoropyridin-4-yl)benzoic acid;

intermediate 2d2: 2-chlorobiphenyl-4-carboxylic acid;

intermediate 2e2: 2′-chloro-2-methoxybiphenyl-4-carboxylic acid,

intermediate 2f2: 3-methoxy-4-(pyrimidin-5-yl)benzoic acid;

intermediate 2g2: 2′-(methoxymethyl)biphenyl-4-carboxylic acid;

intermediate 2h2: 4-(2,6-dimethoxypyridin-3-yl)benzoic acid;

intermediate 2i2: 3-methoxy-4-(2-methoxypyrimidin-5-yl)benzoic acid, rt=3.2 min (gradient A);

intermediate 2j2: 4-(5-methoxypyrazin-2-yl)benzoic acid;

intermediate 2k2: 4-(3-methoxypyrazin-2-yl)benzoic acid;

intermediate 2l2: 4-(2-chloro-4-(dimethylamino)pyrimidin-5-yl)benzoic acid;

intermediate 2m2: 4-(2,6-dimethoxypyrimidin-4-yl)benzoic acid;

intermediate 2n2: 4-(2-methylthiophen-3-yl)benzoic acid;

intermediate 2o2: methyl 2′,6′-dichlorobiphenyl-4-carboxylate;

intermediate 2p2: 2′-chloro-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2q2: 2′-(dimethylamino)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2r2: 3-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2t2: 4-(2-chloro-4-methoxypyrimidin-5-yl)benzoic acid;

intermediate 2u2: 4-(3-methoxypyridin-2-yl)benzoic acid;

intermediate 2v2: 2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2w2: 2′,4′-difluoro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2x2: 2-methyl-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2y2: 3-chloro-4-(pyrimidin-4-yl)benzoic acid;

intermediate 2z2: 2-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2a3: 2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2b3: 4′-fluoro-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2c3: 4-(6-ethoxypyridin-3-yl)benzoic acid;

intermediate 2d3: 4-(6-isopropoxypyridin-3-yl)benzoic acid;

intermediate 2e3: 4-(6-methoxy-2-methylpyridin-3-yl)benzoic acid;

intermediate 2f3: 3-chloro-4-(2-methoxypyrimidin-4-yl)benzoic acid;

intermediate 2g3: 3-chloro-4-(pyrimidin-5-yl)benzoic acid;

intermediate 2h3: 2′,3′-dimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2i3: 3′,4′-dimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2j3: 2′,3′,4′-trimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2k3: 2′,3′,6′-trimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2l3: 3′,5′-dimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2m3: 2′,5′-dimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2n3: 2′-isopropyl-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2o3; 2′-ethyl-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2p3: 4-(2,6-dimethylpyridin-3-yl)benzoic acid;

intermediate 2q3: 4-(2,4-bis(benzyloxy)pyrimidin-5-yl)benzoic acid;

intermediate 2r3: 3-chloro-4-(6-methoxypyridin-3-yl)benzoic acid;

intermediate 2s3: 5-methoxy-6-(2-methoxyphenyl)nicotinic acid;

intermediate 2t3: 5-methoxy-6-(2-methoxyphenyl)nicotinic acid;

intermediate 2u3: 3′-cyano-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2v3: 3′-cyano-2′,4′-bis(2,2,2-trifluoroethoxy)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2w3: 3′-amino-2′-methyl-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2x3: 2′-methyl-3′-(methylsulfonamido)-[1,1′-biphenyl]-4-carboxylic acid was obtained by sulfonylation of methyl 3′-amino-2′-methyl-[1,1′-biphenyl]-4-carboxylate (which was synthesized using general method D, route b) and subsequent saponification. Sulfonylation procedure (as in J. Org. Chem. 2003, 68, 5300-5309): methyl 3′-amino-2′-methylbiphenyl-4-carboxylate (0.83 mmol) was dissolved in dry Et₂O (5 mL) and cooled to 0° C. Then pyridine (5.00 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (5.00 mmol). The reaction was stirred at RT for 2 h. The precipitate was filtered and washed with Et₂O. The organic layer was washed with HCl 1M aqueous solution, brine, dried and concentrated, furnishing 265 mg of desired product as a brown oil in a quantitative yield;

intermediate 2y3: 3′-acetamido-2′-methyl-[1,1′-biphenyl]-4-carboxylic acid was obtained by acetylation of methyl 3′-amino-2′-methyl-[1,1′-biphenyl]-4-carboxylate (which was synthesized using general method D, route b) and subsequent saponification._Acetylation procedure: to a solution of methyl 3′-amino-2′-methylbiphenyl-4-carboxylate (0.83 mmol) in dry DCM (5 mL) under N7 was added acetyl chloride (0.95 mmol), followed by Et₃N (0.91 mmol). The RM was stirred at RT overnight. The RM was then concentrated and the crude purified on silica gel (cyclohexane/EtOAc), furnishing 205 mg of desired product as a yellow oil (87% yield);

intermediate 2z3: 5′-cyano-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid, rt=3.7 min (gradient A);

intermediate 2a4: 5 cyano-2′-methyl-[1,1′-biphenyl]-4-carboxylic acid, rt=3.9 min (gradient A);

intermediate 2b4: 4-(4,6-dimethoxypyridin-3-yl)benzoic acid;

intermediate 2c4: 4′-acetamido-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid was obtained by the nitro group reduction of methyl 2′-methoxy-4′-nitro-[1,1′-biphenyl]-4-carboxylate (which was synthesized using general method D, route b) followed by acetylation with acetyl chloride (procedure described in the synthesis of intermediate 2y3) and saponification;

intermediate 2d4: 3-methoxy-4-(5-methoxypyridin-3-yl)benzoic acid;

intermediate 2e4: 2′,3,6′-trimethoxy-[2,3′-bipyridine]-5-carboxylic acid;

intermediate 2f4: 5′-cyano-2′,3′-dimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2g4: 2′-cyano-4′,5′-di methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2h4: 3′,4′,5′-trimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2i4: 2′-(cyanomethyl)-4′,5′-dimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2j4: 3′,4′-dicyano-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2k4: 5′-cyano-2′-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2l4: 2-fluoro-3′,4′-dimethoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2m4: 4-(2,6-dimethoxypyridin-3-yl)-3-fluorobenzoic acid;

intermediate 2n4: 3-fluoro-4-(6-methoxypyridin-3-yl)benzoic acid;

intermediate 2r4: 4-(3,6-dimethoxypyridazin-4-yl)benzoic acid, rt=3.2 min (gradient A);

intermediate 2s4: 2′-cyano-4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2u4: 3′-cyano-4′-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2v4: 2′-chloro-5′-cyano-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2w4: 2′-cyano-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2x4: 2′-methyl-3′-(N-methylmethylsulfonamido)-[1,1′-biphenyl]-4-carboxylic acid was obtained by sulfonylation of methyl 3′-amino-2′-methyl-[1,1′-biphenyl]-4-carboxylate, followed by sulfonamide N-methylation with iodomethane, and subsequent saponification. Methyl 3′-amino-2′-methyl-[1,1′-biphenyl]-4-carboxylate was synthesized using general method D (route b); sulfonamide N-methylation procedure: in a glass tube was introduced methyl 2′-methyl-3′-(methylsulfonamido)biphenyl-4-carboxylate (0.438 mmol) and sodium hydride (0.570 mmol) in dry DMF (2 mL) at room temperature under argon atmosphere. After 30 minutes at room temperature, iodomethane (1.315 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Brine was then added and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated under reduced pressure, furnishing crude desired product as a pale yellow oil in a quantitative yield; rt=3.4 min (gradient A)

intermediate 2y4: 6-(5-cyano-2-methoxyphenyl)-5-methoxynicotinic acid;

intermediate 2z4: 6-(2,4-dimethoxyphenyl)-5-methoxynicotinic acid;

intermediate 2a5: 6-(2,4-dimethoxyphenyl)nicotinic acid;

intermediate 2f5: 4-(4,6-dimethoxypyrimidin-5-yl)benzoic acid.

Route c is exemplified for the synthesis of intermediate 2g5 3-chloro-4-(2,4-dimethoxypyrimidin-5-yl)benzoic acid Step 1: Synthesis of methyl 3-chloro-4-(2,4-dimethoxypyrimidin-5-yl)benzoate

In a oven dried glass tube were introduced under argon 2-chloro-4-(methoxycarbonyl)phenylboronic acid (2.0 mmol) and 5-iodo-2,4-dimethoxypyrimidine (1.0 mmol). The tube was subjected to three vacuum/argon cycles and toluene (5 mL) was added, followed by a 2M aqueous solution of K₂CO₃ (3.0 mmol). The resulting mixture was degassed (argon bubbling into the solution for 5-10 minutes). Tris(dibenzylideneacetone)dipalladium(0) (5%) and S-Phos (10%) were then added and mixture was heated to 95° C. overnight. The mixture was cooled down to room temperature and then diluted with EtOAc and washed with brine. The aqueous layer was further extracted with EtOAc and the combined organic layers were dried and concentrated. The residue was purified on silica gel (cyclohex/EtOAc), furnishing 143 mg of desired product as a pale yellow solid (93% yield).

Step 2: Saponification Using Same Procedure of 2 h Synthesis

The following intermediates were synthesized from ad-hoc reagents using general method D route c:

intermediate 2h5: 2-fluoro-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2j5: 5-(2-methoxyphenyl)pyrazine-2-carboxylic acid;

intermediate 2k5: 3-methoxy-4-(4-methoxypyridin-3-yl)benzoic acid;

intermediate 2l5: 3-methoxy-4-(6-methoxypyridin-3-yl)benzoic acid;

intermediate 2m5: 3-chloro-4-(2-methoxypyrimidin-5-yl)benzoic acid (exemplified above);

intermediate 2n5: 4-(2,4-dimethoxypyrimidin-5-yl)-3-methoxybenzoic acid;

intermediate 2r4: 4-(3,6-dimethoxypyridazin-4-yl)benzoic acid;

intermediate 2p5: 2′-methoxy-4′-(methylsulfonamido)-[1,1′-biphenyl]-4-carboxylic acid was obtained by the nitro group reduction of methyl 2′-methoxy-4′-nitro-[1,1′-biphenyl]-4-carboxylate (which was synthesized using general method D, route c) followed by sulfonylation with methanesulfonyl chloride (procedure described in the synthesis of intermediate 2x3) and saponification. Nitro reduction procedure: to a solution of methyl 2′-methoxy-4′-nitrobiphenyl-4-carboxylate (1.184 mmol) in anhydrous EtOH (35 ml) was added a slurry of Raney Ni in water (0.4 mL). The mixture was stirred at 50° C. overnight. The RM was filtered on celite, and the solid was washed with MeOH. The filtrate was evaporated to yield desired product which was used without further purification;

intermediate 2q5: 4-(2,6-dimethoxypyridin-3-yl)benzoic acid;

intermediate 2s5: 2-fluoro-4′-(methylsulfonamido)-[1,1′-biphenyl]-4-carboxylic acid was obtained by sulfonylation of methyl 4′-amino-2-fluoro-[1,1′-biphenyl]-4-carboxylate and subsequent saponification. methyl 4′-amino-2-fluoro-[1,1′-biphenyl]-4-carboxylate was synthetized using general method D, route c;

intermediate 2t5: 2-fluoro-3′-(methylsulfonamido)-[1,1′-biphenyl]-4-carboxylic acid was obtained by sulfonylation of methyl 3′-amino-2-fluoro-[1,1′-biphenyl]-4-carboxylate and subsequent saponification. methyl 3′-amino-2-fluoro-[1,1′-biphenyl]-4-carboxylate was synthetized using general method D, route c;

intermediate 2u5: 2′-cyano-2-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

intermediate 2v5: 2′-methoxy-4′-(N-methylmethylsulfonamido)-[1,1′-biphenyl]-4-carboxylic acid was obtained by the nitro group reduction of 2′-methoxy-4′-nitro-[1,1′-biphenyl]-4-carboxylate, followed by sulfonylation with methanesulfonyl chloride, followed by sulfonamide N-methylation with iodomethane, and subsequent saponification; rt=3.7 min (gradient A). Methyl 2′-methoxy-4′-nitro-[1,1′-biphenyl]-4-carboxylate was synthesized using general method D (route c).

Intermediate 2w5 4-(3,6-dimethoxypyridazin-4-yl)-3-fluorobenzoic acid which was obtained from methyl 4-bromo-3-fluorobenzoate and (3,6-dimethoxypyridazin-4-yl)boronic acid using a suzuki coupling procedure described in the literature (J. Org. Chem., 2008, 73, 2176-2181); rt=3.5 min (gradient A).

Unless otherwise stated compounds in examples 2 to 44 were synthesized from intermediate 1a and commercially available carboxylic acids or acyl chlorides using general method C.

Example 2: compound n^(o) 2: (2S,5R)-5-(2-chlorophenyl)-1-(2′-methyl-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 3: compound n^(o) 3: (2S,5R)-1-(3-((4-chlorobenzyl)oxy)-5-methoxybenzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 4: compound n^(o) 4: (2S,5R)-5-(2-chlorophenyl)-1-(2′-fluoro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2b using general method C.

Example 5: compound n^(o) 5: (2S,5R)-5-(2-chlorophenyl)-1-(4′-methyl-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 6: compound n^(o) 6: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-5-phenethoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2c using general method C.

Example 8: compound n^(o) 8: (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 9: compound n^(o) 9: (2S,5R)-5-(2-chlorophenyl)-1-(3-(3,3-diphenylpropoxy)-5-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2d using general method C.

Example 10: compound n^(o) 10: (2S,5R)-5-(2-chlorophenyl)-1-(3′-fluoro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 11: compound n^(o) 11: (2S,5R)-5-(2-chlorophenyl)-1-(3′-methyl-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 12: compound n^(o) 12: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-5-((4-(methylsulfonyl)benzyl)oxy)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2e using general method C.

Example 13: compound n^(o) 13: (2S,5R)-5-(2-chlorophenyl)-1-(3′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 14: compound n^(o) 14: (2S,5R)-5-(2-chlorophenyl)-1-(3,5-dimethoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 15: compound n^(o) 15: (2S,5R)-5-(2-chlorophenyl)-1-(4-(phenoxymethyl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 16: compound n^(o) 16: (2S,5R)-5-(2-chlorophenyl)-1-(4-((2-fluorobenzyl)oxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 17: compound n^(o) 17: (2S,5R)-1-(3-chloro-5-methoxybenzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 18: compound n^(o) 18: (2S,5R)-5-(2-chlorophenyl)-1-(4′-fluoro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 19: compound n^(o) 19: (2S,5R)-5-(2-chlorophenyl)-1-(4-phenethoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 20: compound n^(o) 20: (2S,5R)-5-(2-chlorophenyl)-1-(chroman-3-carbonyl)pyrrolidine-2-carboxylic acid.

Example 21: compound n^(o) 21: (2S,5R)-5-(2-chlorophenyl)-1-(3,5-diethoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 23: compound n^(o) 23: (2S,5R)-5-(2-chlorophenyl)-1-(3-phenethoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 24: compound n^(o) 24: (2S)-1-([1,1′-biphenyl]-4-carbonyl)-4-benzyl-5-phenylpyrrolidine-2-carboxylic acid was synthesized as described in scheme 24.

Example 25: compound n^(o) 25: (2S,5R)-5-(2-chlorophenyl)-1-(1,2,3,4-tetrahydronaphthalene-2-carbonyl)pyrrolidine-2-carboxylic acid.

Example 26: compound n^(o) 26: (2S,5R)-5-(2-chlorophenyl)-1-(4-isobutylbenzoyl)pyrrolidine-2-carboxylic acid.

Example 27: compound n^(o) 27: (2S,5R)-5-(2-chlorophenyl)-1-(2,2-difluorobenzo[d][1,3]dioxole-6-carbonyl)pyrrolidine-2-carboxylic acid.

Example 28: compound n^(o) 28: (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid.

Example 29: compound n^(o) 29: (2S,5R)-5-(2-chlorophenyl)-1-(3-fluoro-5-methoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 30: compound n^(o) 30: (2S,5R)-5-(2-chlorophenyl)-1-(6-phenylnicotinoyl)pyrrolidine-2-carboxylic acid.

Example 31: compound n^(o) 31: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-5-(2-methoxyethoxy)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2f using general method C.

Example 32: compound n^(o) 32: (2S,5R)-5-(2-chlorophenyl)-1-(3′-methoxy-[1,1′-biphenyl]-3-carbonyl)pyrrolidine-2-carboxylic acid.

Example 33: compound n^(o) 33: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-5-(trifluoromethyl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 34: compound n^(o) 34: (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-3-carbonyl)pyrrolidine-2-carboxylic acid.

Example 35: compound n^(o) 35: (2S,5R)-5-(2-chlorophenyl)-1-(4-isopropoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 36: compound n^(o) 36: (2S,5R)-5-(2-chlorophenyl)-1-(3-(3,5-dimethylisoxazol-4-yl) methoxy)-5-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2g using general method C.

Example 37: compound n^(o) 37: (2S,5R)-5-(2-chlorophenyl)-1-(2,3-dihydro-1H-indene-2-carbonyl)pyrrolidine-2-carboxylic acid.

Example 38: compound n^(o) 38: (2S,5R)-5-(2-chlorophenyl)-1-(3-methyl-5-(trifluoromethoxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 39: compound n^(o) 39: (2S,5R)-1-(3-(benzyloxy)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 40: compound n^(o) 40: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 41: compound n^(o) 41: (2S,5R)-5-(2-chlorophenyl)-1-(2-phenylpyrimidine-5-carbonyl)pyrrolidine-2-carboxylic acid.

Example 42: compound n^(o) 42: (2S,5R)-5-(2-chlorophenyl)-1-(4-(trifluoromethoxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 43: compound n^(o) 43: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 44: compound n^(o) 44: 4-((2S,5R)-2-carboxy-5-(2-chlorophenyl)pyrrolidine-1-carbonyl)-2,6-dimethoxypyrimidin-1-ium formate.

Example 45: compound n^(o) 45: (2S,5R)-5-(2-chlorophenyl)-1-(4-phenylbutanoyl)pyrrolidine-2-carboxylic acid.

Example 46: compound n^(o) 46: (2S,5R)-5-(2-chlorophenyl)-1-(3-methyl-5-(trifluoromethyl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 47: compound n^(o) 47: (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5-(3-chloropyridin-2-yl)pyrrolidine-2-carboxylic acid intermediate 1c using general method C.

Example 48: compound n^(o) 48: (2S,5R)-5-(2-chlorophenyl)-1-(3-hydroxy-5-(trifluoromethyl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 49: compound n^(o) 49: (2S,5S)-5-(2-chlorophenyl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1b using general method C.

Example 50: compound n^(o) 50: (2S,5R)-1-(3,5-dimethoxybenzoyl)-5-phenylpyrrolidine-2-carboxylic acid was synthesized from intermediate 1d ((2S,5R)-methyl 5-phenylpyrrolidine-2-carboxylate). 1d was synthesized from commercially available (2S,5R)-1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid using the synthetic steps described in scheme 4.

Example 51: compound n^(o) 51: (S)-5-([1,1′-biphenyl]-3-yl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1using general method C.

Example 52: compound n^(o) 52: (2S,5R)-5-(2-chlorophenyl)-1-(3-phenylpropanoyl)pyrrolidine-2-carboxylic acid.

Example 53: compound n^(o) 53: (2S,5S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1b using general method C.

Example 54: compound n^(o) 54: (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5-(pyridin-2-yl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1f using general method C.

Example 55: compound n^(o) 55: (2S,5R)-5-(2-chlorophenyl)-1-(5-phenylpicolinoyl)pyrrolidine-2-carboxylic acid.

Example 57: compound n^(o) 57: (2S,5R)-5-(2-fluorophenyl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1g using general method C.

Example 58: compound n^(o) 58: (2S,5R)-1-(2-([1,1′-biphenyl]-4-yl)acetyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 59: compound n^(o) 59: (2R,5S)-1-([1,1′-biphenyl]-4-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid was synthesized from intermediate 1h using general method C. 1h was synthesized from commercially available (2R,5S)-1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid using the synthetic steps described in scheme 4.

Example 60: compound n^(o) 60: (2S,5R)-5-phenyl-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1d using general method C.

Example 61: compound n^(o) 61: (2R,5S)-5-phenyl-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1h using general method C.

Example 62: compound n^(o) 62: (2S,5R)-1-(3-methoxybenzoyl)-5-(2-methoxyphenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1i using general method C.

Example 63: compound n^(o) 63: (2R,5S)-5-(2-chlorophenyl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1j using general method C.

Example 64: compound n^(o) 64: (2R,5R)-5-(2-chlorophenyl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1j using general method C.

Example 65: compound n^(o) 65: (2S)-5-(4-chlorophenyl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1k using general method C.

Example 66: compound n^(o) 66: (2S)-5-([1,1′-biphenyl]-4-yl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1l using general method C.

Example 67: compound n^(o) 67: (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylate was synthesized using general method C without the last saponification step.

Example 68: compound n^(o) 68: (2S)-5-(2-chlorobenzyl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1m using general method C.

Example 69: compound n^(o) 69: (2S)-5-cyclohexyl-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1n using general method C.

Example 70: compound n^(o) 70: (2S,5R)-5-(2-chlorophenyl)-1-(2-(3-methoxyphenyl)acetyl)pyrrolidine-2-carboxylic acid.

Example 71: compound n^(o) 71: (2S,5S)-5-(2-chlorophenyl)-1-(3 5-dimethoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1b using general method C.

Example 72: compound n^(o) 72: (2S,5R)-5-([1,1′-biphenyl]-2-yl)-1-(3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1o using general method C.

Example 74: compound n^(o) 74: 2-((2S,5R)-5-(2-chlorophenyl)-1-(3-methoxybenzoyl)pyrrolidin-2-yl)acetic acid. Compound n° 40 was reacted with ethyl chloroformate (1.03 eq) in THF in the presence of triethylamine (1.03 eq) and then was added a solution of diazomethane in diethyl ether (2 eq), the mixture was stirred at RT for 2.5 days. Reaction mixture was quenched with a 10% aqueous solution of citric acid and diluted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, then concentrated in vacuo. The residue was dissolved in MeOH and silver benzoate (1 eq) and triethylamine (2 eq) were added. The RM was stirred at RT for 45 min and diluted with AcOEt, washed with a saturated aqueous solution of sodium bicarbonate and brine 1M aqueous HCl, dried over anhydrous MgSO₄ and evaporated to dryness to yield title compound.

Example 75: compound n^(o) 75: (2S,5R)-5-(2-chlorophenyl)-1-(6-phenylpyrimidine-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 76: compound n^(o) 77: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2-chlorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 77: compound n^(o) 78: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2-methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 78: compound n^(o) 79: (2S,5R)-5-(2-chlorophenyl)-1-(6-(3-fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 79: compound n^(o) 80: (2S,5R)-5-(2-chlorophenyl)-1-(6-(3-methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 80: compound n^(o) 81: (2S,5R)-5-(2-chlorophenyl)-1-(6-(4-methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 81: compound n^(o) 82: (2S,5R)-5-(2-chlorophenyl)-1-(6-(4-fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 82: compound n^(o) 83: (2S,5R)-5-(2-chlorophenyl)-1-(2-(2-chlorophenyl)pyrimidine-5-carbonyl)pyrrolidine-2-carboxylic acid.

Example 83: compound n^(o) 84: (2S,5R)-5-(2-chlorophenyl)-1-(2-methyl-6-phenylnicotinoyl)pyrrolidine-2-carboxylic acid.

Example 84: compound n^(o) 88: (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was was synthesized from intermediates 1a and 2u1 using general method C.

Example 85: compound n^(o) 89: (2S,5R)-1-(4-((4-chlorophenoxy)methyl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 86: compound n^(o) 91: (2S,5R)-5-(2-chlorophenyl)-1-(4-((4-methoxyphenoxy)methyl)benzoyl)pyrrolidine-2-carboxylic acid

Example 87: compound n^(o) 92: (2S,5R)-1-(4-((2-chlorophenoxy)methyl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1b using general method C.

Example 88: compound n^(o) 95: (2S,5R)-1-(4-((3-chlorophenoxy)methyl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 89: compound n^(o) 96: (2S,5R)-5-(2-chlorophenyl)-1-(4-((p-tolyloxy)methyl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 90: compound n^(o) 99: (2S,5R)-5-(2-chlorophenyl)-1-(4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 91: compound n^(o) 102: (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-4-ylmethoxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 92: compound n^(o) 104: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-methyl-1H-pyrazol-1-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 93: compound n^(o) 105: (2S,5R)-5-(2-chlorophenyl)-1-(4-(isoxazol-5-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 94: compound n^(o) 106: (2S,5R)-1-(4-(4H-1,2,4-triazol-4-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 95: compound n^(o) 107: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-(p-tolyl)-1H-1,2,3-triazol-1-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 96: compound n^(o) 108: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-oxo-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 97: compound n^(o) 109: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 98: compound n^(o) 110: (2S,5R)-1-(4-(1H-pyrazol-1-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 99: compound n^(o) 111: (2S,5R)-5-(2-chlorophenyl)-1-(4-(oxazol-5-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 100: compound n^(o) 112: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3,5-dimethyl-1H-pyrazol-1-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 101: compound n^(o) 113: (2S,5R)-5-(2-chlorophenyl)-1-(2′,5′-dichloro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2i using general method C.

Example 102: compound n^(o) 114: (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2j using general method C.

Example 103: compound n^(o) 115: (2S,5R)-5-(2-chlorophenyl)-1-(4-(furan-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2k using general method C.

Example 104: compound n^(o) 116: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2l using general method C.

Example 105: compound n^(o) 117: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3-fluoropyridin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2m using general method C.

Example 106: compound n^(o) 118: (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2n using general method C.

Example 107: compound n^(o) 119: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-(dimethylamino)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2o using general method C.

Example 108: compound n^(o) 120: (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyridin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2p using general method C.

Example 109: compound n^(o) 121: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-methylpyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2q using general method C.

Example 110: compound n^(o) 122: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2r using general method C.

Example 111: compound n^(o) 123: (2S,5R)-5-(2-chlorophenyl)-1-(4′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2s using general method C.

Example 112: compound n^(o) 124: (2S,5R)-5-(2-chlorophenyl)-1-(4′-cyano-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2t using general method C.

Example 113: compound n^(o) 125: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2u using general method C.

Example 114: compound n^(o) 126: (2S,5R)-1-(4′-chloro-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2v using general method C.

Example 115: compound n^(o) 127: (2S,5R)-1-(3′-chloro-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2w using general method C.

Example 116: compound n^(o) 128: (2S,5R)-1-(2′-chloro-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2x using general method C.

Example 117: compound n^(o) 129: (2S,5R)-5-(2-chlorophenyl)-1-(4′-(methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2y using general method C.

Example 118: compound n^(o) 130: (2S,5R)-5-(2-chlorophenyl)-1-(3′-(methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2z using general method C.

Example 119: compound n^(o) 131: (2S,5R)-5-(2-chlorophenyl)-1-(2′-(methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2a1 using general method C.

Example 120: compound n^(o) 132: (2S,5R)-5-(2-chlorophenyl)-1-(4-(naphthalen-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2b1 using general method C.

Example 121: compound n^(o) 133: (2S,5R)-5-(2-chlorophenyl)-1-(3′,5′-difluoro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2c1 using general method C.

Example 122: compound n^(o) 134: (2S,5R)-5-(2-chlorophenyl)-1-(2′-hydroxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2d1 using general method C.

Example 123: compound n^(o) 135: (2S,5R)-5-(2-chlorophenyl)-1-(2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2e1 using general method C.

Example 124: compound n^(o) 136: (2S,5R)-1-(24benzyloxy)-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 125: compound n^(o) 137: (2S,5R)-5-(2-chlorophenyl)-1-(2′-phenoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 126: compound n^(o) 138: (2S,5R)-5-(2-chlorophenyl)-1-(2′-isopropoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 127: compound n^(o) 139: (2S,5R)-5-(2-chlorophenyl)-1-(2′-isobutoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 128: compound n^(o) 140: (2S,5R)-5-(2-chlorophenyl)-1-(2′-(cyclopropylmethoxy)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 129: compound n^(o) 141: (2S,5R)-5-(2-chlorophenyl)-1-(24(4-fluorobenzyl)oxy)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 130: compound n^(o) 142: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-chloropyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2l1 using general method C.

Example 131: compound n^(o) 143: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-fluoropyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2m1 using general method C.

Example 132: compound n^(o) 149: (2S,5R)-5-(2-chlorophenyl)-1-(4-(thiophen-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2n1 using general method C.

Example 133: compound n^(o) 150: (2S,5R)-5-(2-chlorophenyl)-1-(4-cyclohexylbenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2o1 using general method C.

Example 134: compound n^(o) 152: (2S,5R)-5-(2-chlorophenyl)-1-(9-oxo-9H-fluorene-2-carbonyl)pyrrolidine-2-carboxylic acid.

Example 135: compound n^(o) 153: (2S,5R)-5-(2-chlorophenyl)-1-(2′-(methylsulfonyl)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2p1 using general method C.

Example 136: compound n^(o) 155: (2S,5R)-5-(2-chlorophenyl)-1-(9-methyl-9H-carbazole-2-carbonyl)pyrrolidine-2-carboxylic acid.

Example 137: compound n^(o) 156: (2S,5R)-5-(2-chlorophenyl)-1-(4-phenoxybenzoyl)pyrrolidine-2-carboxylic acid.

Example 138: compound n^(o) 157: (2S,5R)-1-(4-benzylbenzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 139: compound n^(o) 158: (2S,5R)-1-(4-benzoylbenzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Example 140: compound n^(o) 159: (2S,5R)-5-(2-chlorophenyl)-1-(4-(pyrimidin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2q1 using general method C.

Example 141: compound n^(o) 160: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6-dimethoxypyrimidin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2r1 using general method C.

Example 142: compound n^(o) 161: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4-dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2s1 using general method C.

Example 143: compound n^(o) 162: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2t1 using general method C.

Example 144: compound n^(o) 168: (2S,5R)-5-(2-chlorophenyl)-1-(cyclohexanecarbonyl)pyrrolidine-2-carboxylic acid.

Example 145: compound n^(o) 169: (2S,5R)-5-(2-chlorophenyl)-1-(4-methylpentanoyl)pyrrolidine-2-carboxylic acid.

Example 146: compound n^(o) 172: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4-methylpiperidin-1-yl)-3-nitrobenzoyl)pyrrolidine-2-carboxylic acid.

Example 147: compound n^(o) 173: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-oxopiperidin-1-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 148: compound n^(o) 174: (2S,5R)-5-(2-chlorophenyl)-1-(3-methyl-4-morpholinobenzoyl)pyrrolidine-2-carboxylic acid.

Example 149: compound n^(o) 175: (2S,5R)-5-(2-chlorophenyl)-1-(4-(piperidin-1-yl)benzoyl)pyrrolidine-2-carboxylic acid.

Example 150: compound n^(o) 176: (2S,5R)-5-(2-chlorophenyl)-1-(4-morpholinobenzoyl)pyrrolidine-2-carboxylic acid.

Example 151: compound n^(o) 177: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-cyanophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid.

Example 152: compound n^(o) 178: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4-chlorophenyl)cyclohexanecarbonyl)pyrrolidine-2-carboxylic acid.

Example 153: compound n^(o) 179: (2S,5R)-5-(2-chlorophenyl)-1-(4-phenylcyclohexanecarbonyl)pyrrolidine-2-carboxylic acid.

Example 154: compound n^(o) 183: ((2R,5S)-2-(2-chlorophenyl)-5-(1H-tetrazol-5-yl)pyrrolidin-1-yl)(2′-methoxy-[1,1′-biphenyl]-4-yl)methanone:

Step 1: Synthesis of (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxamide

In a glass tube containing compound n^(o) 1 (0.2 g, 0.459 mmol) in THF (5 mL) were added CDI (0.167 g, 0.11 mmol). The RM was stirred at RT for 30 mn, then NH₃ bubbling in the RM for 1 mn. The RM was diluted with HCl 1M and extracted with EtOAc. The organic layer was dried overnight over MgSO4. The concentrated in vacuo and the residue (164 mg) diluted in MeCN and passed through a new PE-AX (2 g) cartridge. The filtrate was concentrated to yield title intermediate. Y: 0.14 g (70%), P>80%, rt=4.08 nm (gradient A).

Step 2: Synthesis of (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carbonitrile

In a 50 mL round bottom flask containing (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxamide (0.14 g, 0.322 mmol) were added DMF (3.22 mL). The RM was degassed and placed under Ar. Cyanuric chloride (0.059 g, 0.322 mmol) was added and the RM stirred at RT for 90 mn. The RM was diluted with NaHCO₃ (aqueous saturated solution) and extracted with AcOEt. The organic phase was washed with brine (2×), dried over MgSO₄ filtered and concentrated to afford 126 mg of title product. Y: 0.126 g (94%), P>80%, rt=4.53 mn (gradient A), (M+H)⁺=417/419.

Step 3: Synthesis of Compound n^(o) 183

In a oven-dried glass tube were added under Ar sodium azide (0.086 g, 1.330 mmol) and THF (5 mL). Were added successively aluminium chloride (0.101 g, 0.756 mmol) and (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carbonitrile (0.126 g, 0.302 mmol) diluted in 1 mL THF. The RM was heated at 60° C. overnight. Sodium azide (0.086 g, 1.33 mmol) and aluminium chloride (0.101 g, 0.756 mmol) were added and the RM stirred at 60° C. for another 7 h. The RM was allowed to reach RT and quenched with HCl 6N and extracted with AcOEt (2×). The organic layer was dried over MgSO₄, filtered and concentrated to afford 160 mg of crude product as a yellow oil. Crude was purified by flash chromatography (DCM/MeOH:95/5) and SPE using a PEAX cartridge and elution with ACN, then ACN+HCl. Crude in MeCN solution from the PEAX fractions were concentrated in vacuo. Residue lyophilized in ACN/Water (2 mL/1 mL). Y: 13 mg (9%), P=100%, rt=5.19 mn (gradient B), (M+H)⁺=460.

Example 155: compound n^(o) 184: (2R,5S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1j and 2h using general method C.

Example 160: compound n^(o) 189: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2-fluorophenyl)nicotinoyl)pyrrolidine-2-carboxylic acid.

Example 162: compound n^(o) 191: (2S,5R)-5-(2-chlorophenyl)-1-(5-methoxy-6-phenylnicotinoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2i1 using general method C.

Example 163: compound n^(o) 192: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-methoxyphenoxy)benzoyl)pyrrolidine-2-carboxylic acid.

Example 164: compound n^(o) 193: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3-methoxypyridin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2j1 using general method C.

Example 165: compound n^(o) 194: (2S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-4,4-dimethylpyrrolidine-2-carboxylic acid was synthesized from intermediates 1p and 2h using general method C.

Example 166: compound n^(o) 195: (2S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-4-methylpyrrolidine-2-carboxylic acid was synthesized from intermediates 1q and 2h using general method C.

Example 167: compound n^(o) 196: (2S,5R)-5-(2-chlorophenyl)-1-(2-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2k1 using general method C.

Example 168: compound n^(o) 197: (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2v1 using general method C.

Example 169: compound n^(o) 198: (2S,5R)-5-(2-chlorophenyl)-1-(2′,6′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2w1 using general method C.

Example 170: compound n^(o) 199: (2S,5R)-5-(2-chlorophenyl)-1-(2′,4′-dichloro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2x1 using general method C.

Example 171: compound n^(o) 200: (2S,5R)-5-(2-chlorophenyl)-1-(2′-(trifluoromethyl)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2y1 using general method C.

Example 172: compound n^(o) 201: (2S,5R)-5-(2-chlorophenyl)-1-(2,2′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2z1 using general method C.

Example 173: compound n^(o) 202: (2S,5R)-1-(4′-chloro-2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2a2 using general method C.

Example 174: compound n^(o) 203: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4-methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2b2 using general method C.

Example 175: compound n^(o) 204: (2S,5R)-5-(2-chlorophenyl)-1-(2′,4′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2c2 using general method C.

Example 176: compound n^(o) 205: (2S,5R)-1-([1,1′-biphenyl]-4-carbonyl)-5-(pyridin-3-yl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1r using general method C.

Example 177: compound n^(o) 206: (2R,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1j using general method C.

Example 178: compound n^(o) 207: (2S,5R)-5-(2-chlorophenyl)-1-(1-phenyl-1H-benzo[d]imidazole-5-carbonyl)pyrrolidine-2-carboxylic acid.

Example 179: compound n^(o) 208: (2S,5R)-methyl 5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate was obtained in step 1 of general method C.

Example 180: compound n^(o) 217: (2S,4S,5S)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-4-(phenylsulfonyl)pyrrolidine-2-carboxylic acid was synthesized using the methodology described in scheme 9.

Example 181: compound n^(o) 220: (2S,5R)-5-(2-chlorophenyl)-4-cyano-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the methodology described in scheme 9.

Example 182: compound n^(o) 224: (2S,5R)-1-(2-chloro-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2d2 using general method C.

Example 183: compound n^(o) 225: (2S,5R)-1-(2′-chloro-2-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2e2 using general method C.

Example 184: compound n^(o) 226: (2S,5R)-5-(2-chlorophenyl)-1-(2′-(2-methoxyethoxy)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and 2′-(2-methoxyethoxy)biphenyl-4-carboxylic acid which was obtained by saponification of methyl 2′-(2-methoxyethoxy)biphenyl-4-carboxylate. The latter intermediate was prepared using Mitsunobu chemistry:

To a solution of methyl 2′-hydroxybiphenyl-4-carboxylate (300 mg, 1.31 mmol), triphenylphosphine (517 mg, 1.97 mmol) and 2-methoxyethanol (130 μL, 1.64 mmol) in THF (12.5 mL) was added slowly diisopropylazodicarboxylate (388 μL, 1.97 mmol) at 0° C. The mixture was stirred at RT overnight and the reaction was quenched with methanol. The reaction mixture was diluted with water and extracted with DCM (25 mL). The organic layer was washed with water, dried and concentrated in vacuo. Crude was purified by column chromatography (cyclohexane/EtOAc=1/1) to yield 2′-(2-methoxyethoxy)biphenyl-4-carboxylate as a yellow oil. Y: 450 mg (78%), P: 65%, rt=2.5 mn (gradient A), Rf (cyclohexane/EtOAc=95/5)=0.75.

Example 185: compound n^(o) 230: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(pyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2f2 using general method C.

Example 186: compound n^(o) 231: (2S,5R)-1-(2′-carbamimidoyl-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid.

Step 1

To a solution of compound n^(o) 197 precursor (2S,5R)-methyl 5-(2-chlorophenyl)-1-(2′-cyano-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate (100 mg, 0.225 mmol) and hydroxylamine hydrochloride (32 mg, 0.45 mmol) in EtOH (1 mL) was triethylamine (64 μL, 0.45 mmol) dropwise at room temperature. The mixture was stirred at reflux for 2 days. The mixture was cooled to RT and concentrated. Crude was purified by column chromatography (DCM/MeOH=98/2) to yield (2S,5R)-methyl5-(2-chlorophenyl)-1-(2′-((E)-N′-hydroxycarbamimidoyl)biphenylcarbonyl)pyrrolidine-2-carboxylate as a colorless solid. Y: 113 mg (63%), P: >80%, rt=3.6 mn (gradient A), Rf (DCM/MeOH=9/1)=0.3.

Step 2

A solution of (2S,5R)-methyl5-(2-chlorophenyl)-1-(2′-((E)-N′-hydroxycarbamimidoyl)biphenylcarbonyl)pyrrolidine-2-carboxylate in (EtOH/THF/AcOH=1/1/0.025) (2 mL) was hydrogenated at RT for 45 min. under atmospheric pressure of H₂ using a slurry solution of Raney nickel catalyst in water (2 vacuum/N2 cycles and then 2 vacuum/H₂ cycles). The catalyst was filtered off over Celite and the filtrate was concentrated in vacuo to yield (2S,5R)-methyl 1-(2′-carbamimidoylbiphenylcarbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylate as a greenish solid. Y: 64 mg (99%), P: 70%, rt=3.5 mn (gradient A).

Step 3

(2S,5R)-methyl 1-(2′-carbamimidoylbiphenylcarbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylate was saponified as exemplified in general method C to provide compound n^(o) 231.

Example 187: compound n^(o) 232: (2S,5R)-5-(2-fluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g using general method C.

Example 188: compound n^(o) 233: (2S,5R)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(o-tolyppyrrolidine-2-carboxylic acid was synthesized from intermediates 1s using general method C.

Example 189: compound n^(o) 234: (2S,5R)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-methoxyphenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1i using general method C.

Example 190: compound n^(o) 235: (2S,5R)-5-(2-chlorophenyl)-1-(2′-(methoxymethyl)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2g2 using general method C.

Example 191: compound n^(o) 236: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6-dimethoxypyridin-3-yl)benzo yl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2h2 using general method C.

Example 192: compound n^(o) 237: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(2-methoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2i2 using general method C.

Example 193: compound n^(o) 238: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-methoxypyrazin-2-yl)benzo yl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2j2 using general method C.

Example 194: compound n^(o) 239: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-(2-methoxyethoxy)pyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and 4-(2-(2-methoxyethoxy)pyridin-3-yl)benzoic acid which was obtained by saponification of methyl 4-(2-(2-methoxyethoxy)pyridin-3-yl)benzoate. The latter intermediate was prepared using Mitsunobu chemistry as described for the synthesis of compound n^(o) 226.

Example 195: compound n^(o) 240: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3-methoxypyrazin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2k2 using general method C.

Example 196: compound n^(o) 241: (2S,5R)-1-(4-(2-chloro-4-(dimethylamino)pyrimidin-5-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 212 using general method C.

Example 197: compound n^(o) 242: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6-dimethoxypyrimidin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2m2 using general method C.

Example 198: compound n^(o) 227: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-methylthiophen-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2n2 using general method C and further purified by preparative HPLC.

Example 199: compound n^(o) 228: (2S,5R)-5-(2-chlorophenyl)-1-(2′,6′-dichloro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2o2 using general method C.

Example 200: compound n^(o) 229: (2S,5R)-1-(2′-chloro-4′-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2p2 using general method C.

Example 201: compound n^(o) 243: (2S,5R)-5-(2-chlorophenyl)-1-(2′-(dimethylamino)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2q2 using general method C.

Example 202: compound n^(o) 246: (2S,5R)-5-(2-fluorophenyl)-1-(4-(2-methoxypyridin-3-yl)benzo yl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g and 2r using general method C.

Example 203: compound n^(o) 247: (2S,5R)-1-(4-(2,4-dimethoxypyrimidin-5-yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g and 2s1 using general method C.

Example 204: compound n^(o) 249: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2r2 using general method C.

Example 205: compound n^(o) 269: (2S,5R)-1-(4-(2,6-dimethoxypyridin-3-yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g and 2h2 using general method C.

Example 206: compound n^(o) 261: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(4-methylpiperidin-1-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 3-methoxy-4-(4-methylpiperidin-1-yl)benzoic acid using general method C (condition B). The synthesis of 3-methoxy-4-(4-methylpiperidin-1-yl)benzoic acid is depicted in scheme 11.

Example 207: compound n^(o) 272: (2S,5R)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-phenylpyrrolidine-2-carboxylic acid was synthesized from intermediates 1t and 2h using general method C (condition A).

Example 208: compound n^(o) 273: (2S,5R)-5-(3-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1u and 2h using general method C (condition A).

Example 209: compound n^(o) 274: (2S,5R)-5-(4-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1v and 2h using general method C (condition A).

Example 210: compound n^(o) 275: (2S,5R)-5-(3-fluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1w and 2h using general method C (condition A).

Example 211: compound n^(o) 276: (2S,5R)-5-(4-fluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1x and 2h using general method C (condition A).

Example 212: compound n^(o) 278: (2S,5R)-4-acetyl-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from (2S,4S,5R)-methyl 4-acetyl-5-(2-chlorophenyl)pyrrolidine-2-carboxylate using the same dipolar cycloaddition methodology as shown in scheme 9, except for the last step (Me₃SnOH (10 eq), DCE, 90° C.) instead of (TFA, DCM).

Example 213: compound n^(o) 279: (2S,4S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid was synthesized from (2S,4S,5R)-4-tert-butyl 2-methyl 5-(2-chlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2,4-dicarboxylate which was obtained using the dipolar cycloaddition methodology shown in scheme 9. Last steps to perform the synthesis of compound n^(o) 279 are depicted in scheme 14.

Example 214: compound n^(o) 280: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2-methoxypyrimidin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2s2 using general method C (condition B).

Example 215: compound n^(o) 281: (2S,5R)-5-cyclohexyl-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1y and 2h using general method C (condition B).

Example 216: compound n^(o) 283: (2S,5R)-1-(4-(2-chloro-4-methoxypyrimidin-5-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2t2 using general method C (condition B).

Example 217: compound n^(o) 284: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3-methoxypyridin-2-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2u2 using general method C (condition B).

Example 218: compound n^(o) 285: (2R,5R)-5-(2-fluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1z and 2h using general method C (condition A).

Example 219: compound n^(o) 286: (2S,5S)-5-(2-fluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a1 and 2h using general method C (condition A).

Example 220: compound n^(o) 287: (2R,5S)-5-(2-fluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1b1 and 2h using general method C (condition A).

Example 221: compound n^(o) 288: (2S,5R)-5-(2-chlorophenyl)-1-(2-(trifluoromethyl)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2v2 using general method C (condition B).

Example 222: compound n^(o) 289: (2S,5R)-5-(2-chlorophenyl)-1-(2′,4′-difluoro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2w2 using general method C (condition B).

Example 223: compound n^(o) 290: (2S,5R)-5-(2-chlorophenyl)-1-(2-methyl-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2x2 using general method C (condition B).

Example 224: compound n^(o) 291: (2S,5R)-5-(2,6-difluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1c1 and 2h using general method C (condition A).

Example 225: compound n^(o) 292: (2S,5R)-5-(2,4-difluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1d1 and 2h using general method C (condition A).

Example 226: compound n^(o) 293: (2S,5R)-5-(2,4-dichlorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1e1 and 2h using general method C (condition A).

Example 227: compound n^(o) 294: (2S,5R)-5-isobutyl-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1f1 and 2h using general method C (condition A).

Example 228: compound n^(o) 295: (2S,5R)-5-isopropyl-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g1 and 2h using general method C (condition A).

Example 229: compound n^(o) 296: (2S,5R)-1-(3-chloro-4-(pyrimidin-4-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2y2 using general method C (condition B).

Example 230: compound n^(o) 297: (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2z2 using general method C (conditions B).

Example 231: compound n^(o) 298: (2S,5R)-5-(2-chlorophenyl)-1-(2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2a3 using general method C (conditions B).

Example 232: compound n^(o) 299: (2S,5R)-5-(2-chlorophenyl)-1-(4′-fluoro-2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2b3 using general method C (conditions B).

Example 233: compound n^(o) 300: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-ethoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2c3 using general method C (conditions B).

Example 234: compound n^(o) 301: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-isopropoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2d3 using general method C (condition B).

Example 234: compound n^(o) 302: (2S,5R)-5-(2-chlorophenyl)-1-(4-(6-methoxy-2-methylpyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2e3 using general method C (condition B).

Example 235: compound n^(o) 303: (2S,5R)-1-(3-chloro-4-(2-methoxypyrimidin-4-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2f3 using general method C (condition B).

Example 236: compound n^(o) 304: (2S,5R)-1-(3-chloro-4-(pyrimidin-5-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2g3 using general method C (condition B).

Example 237: compound n^(o) 305: (2S,5R)-5-(2-chlorophenyl)-4-cyano-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-3-methylpyrrolidine-2-carboxylic acid was synthesized using the 1,3-dipolar cycloaddition shown in scheme 9.

Example 238: compound n^(o) 306: (2S,4S,5R)-5-(2-chlorophenyl)-4-cyano-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-4-methylpyrrolidine-2-carboxylic acid was synthesized using the 1,3-dipolar cycloaddition shown in scheme 9.

Example 239: compound n^(o) 307: (2S,5R)-5-(2-chlorophenyl)-1-(2′,3′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2h3 using general method C (condition B).

Example 240: compound n^(o) 308: (2S,5R)-5-(2-chlorophenyl)-1-(3′,4′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2i3 using general method C (condition B).

Example 241: compound n^(o) 309: (2S,5R)-5-(2-chlorophenyl)-1-(2′,3′,4′-trimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2j3 using general method C (condition B).

Example 242: compound n^(o) 310: (2S,5R)-5-(2-chlorophenyl)-1-(2′,3′,6′-trimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2k3 using general method C (condition B).

Example 243: compound n^(o) 311: (2S,5R)-5-(2-chlorophenyl)-1-(3′,5′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2j3 using general method C (condition B).

Example 244: compound n^(o) 312: (2S,5R)-5-(2-chlorophenyl)-1-(2′,5′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2m3 using general method C (condition B).

Example 245: compound n^(o) 313: (2S,5R)-5-(2-chlorophenyl)-1-(2′-isopropyl-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2n3 using general method C (condition B).

Example 246: compound n^(o) 314: (2S,5R)-1-(2,2′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g and 2z1 using general method C (condition B).

Example 247: compound n^(o) 315: (2S,5R)-1-(2-fluoro-2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g and 2h5 using general method C (condition B).

Example 248: compound n^(o) 316: (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2h5 using general method C (condition B).

Example 249: compound n^(o) 318: (2S,5R)-5-cyclopentyl-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1h1 and 2h using general method C (condition A).

Example 250: compound n^(o) 319: (2S,5R)-5-(2-chlorophenyl)-1-(2′-ethyl-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2o3 using general method C (condition B).

Example 251: compound n^(o) 320: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6-dimethylpyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2p3 using general method C (condition B).

Example 252: compound n^(o) 321: (2S,5R)-1-(4-(2,4-bis(benzyloxy)pyrimidin-5-yl)benzo y1)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2q3 using general method C (conditions B).

Example 253: compound n^(o) 322: (2S,5R)-1-([1,1′:4′,1″-terphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1,1′:4′,1″-terphenyl]-4-carboxylic acid using general method C (conditions B).

Example 254: compound n^(o) 323: (2S,5R)-5-(2-chlorophenyl)-1-(4′-propyl-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 4′-propyl-[1,1′-biphenyl]-4-carboxylic acid using general method C (conditions B).

Example 255: compound n^(o) 324: (2S,5R)-1-(4′-(tert-butyl)-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 4′-(tert-butyl)-[1,1′-biphenyl]-4-carboxylic acid using general method C (conditions B).

Example 256: compound n^(o) 325: (2S,5R)-1-(3-chloro-4-(2,4-dimethoxypyrimidin-5-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2g5 using general method C (conditions B).

Example 257: compound n^(o) 326: (2S,5R)-5-(2-chlorophenyl)-1-(5-(2-methoxyphenyl)pyrazine-2-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2j5 using general method C (conditions B).

Example 258: compound n^(o) 327: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(4-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2k5 using general method C (conditions B).

Example 259: compound n^(o) 328: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(6-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2l5 using general method C (conditions B).

Example 260: compound n^(o) 329: (2S,5R)-1-(3-chloro-4-(2-methoxypyrimidin-5-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2m5 using general method C (conditions B).

Example 261: compound n^(o) 330: (2S,5R)-1-(3-chloro-4-(6-methoxypyridin-3-yl)benzoyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2r3 using general method C (conditions B).

Example 262: compound n^(o) 331: (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-(4-chlorophenyl)thiazol-2-yl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(4-(4-chlorophenyl)thiazol-2-yl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 263: compound n^(o) 332: (2S,5R)-5-(2-fluorophenyl)-1-(5-methoxy-6-(2-methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g and 2s3 using general method C (conditions B).

Example 264: compound n^(o) 333: (2S,5R)-1-(1-(benzo[d]oxazol-2-yl)piperidine-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(benzo[d]oxazol-2-yl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 265: compound n^(o) 334: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(pyrrolidin-1-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as shown in scheme 11, replacing 4-methylpiperidine with pyrrolidine.

Example 266: compound n^(o) 335: (2S,5R)-5-(2-chlorophenyl)-1-(5-methoxy-6-(2-methoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2t3 using general method C (conditions B).

Example 267: compound n^(o) 336: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-methoxyphenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as shown in scheme 13 replacing 2-cyano-4-trifluoromethyl-bromobenzene with 2-methoxy-bromobenzene.

Example 268: compound n^(o) 337: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,4-dimethoxypyrimidin-5-yl)-3-methoxybenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2n5 using general method C (conditions B).

Example 269: compound n^(o) 338: (2S,5R)-5-(2-bromophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1i1 and 2h using general method C (conditions A).

Example 270: compound n^(o) 339: (2S,5R)-5-(2-chlorophenyl)-1-(3′-cyano-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 3′-cyano-[1,1′-biphenyl]-4-carboxylic acid using general method C (conditions B).

Example 271: compound n^(o) 340: (2S,5R)-5-(2-chlorophenyl)-1-(3′-cyano-2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2u3 using general method C (conditions A).

Example 272: compound n^(o) 341: (2S,5R)-5-(2-chlorophenyl)-1-(3′-cyano-2′,4′-bis(2,2,2-trifluoroethoxy)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2v3 using general method C (conditions B).

Example 273: compound n^(o) 342: (2S,5R)-1-(3′-amino-2′-methyl-[ 1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2w3 using general method C (conditions B).

Example 274: compound n^(o) 343: (2S,5R)-5-(2-chlorophenyl)-1-(2′-methyl-3′-(methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2x3 using general method C (conditions B).

Example 275: compound n^(o) 344: (2S,5R)-1-(3′-acetamido-2′-methyl-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2y3 using general method C (conditions B).

Example 276: compound n^(o) 345: (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2z3 using general method C (conditions B).

Example 277: compound n^(o) 346: (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′-methyl-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2a4 using general method C (conditions B).

Example 278: compound n^(o) 347: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6-dimethoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2b4 using general method C (conditions B).

Example 279: compound n^(o) 348: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3,6-dimethoxypyridazin-4-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2r4 using general method C (conditions B).

Example 280: compound n^(o) 349: (2S,5S)-5-isopentyl-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1j1 and 2h using general method C (conditions A).

Example 281: compound n^(o) 350: (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-4′-(methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2p5 using general method C (conditions B).

Example 282: compound n^(o) 351: (2S,5R)-1-(4′-acetamido-2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2c4 using general method C (conditions B).

Example 283: compound n^(o) 352: (2S,5R)-1-(3′-carbamimidoyl-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3′-cyanobiphenylcarbonyl)pyrrolidine-2-carboxylate which was obtained from intermediate 1a and commercial 3′-cyanobiphenyl-4-carboxylic acid using general method C (conditions B).

Step 1:

To a solution of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3′-cyanobiphenylcarbonyl)pyrrolidine-2-carboxylate (1.0 mmol) and hydoxylamine hydrochloride (2.0 mmol) in dry EtOH (5 mL) under N₂ was added NEt₃ (2.0 mmol) dropwise at RT. The mixture was stirred under reflux overnight. The mixture was cooled down to RT, concentrated and purified on silica gel (cyclohex/EtOAc), furnishing 300 mg of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3′-((E)-N′-hydroxycarbamimidoyl)biphenylcarbonyl)pyrrolidine-2-carboxylate as a white solid (60% yield).

Step 2:

A solution of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3′-((E)-N′-hydroxycarbamimidoyl)biphenylcarbonyl)pyrrolidine-2-carboxylate (0.42 mmol) in EtOH/THF/AcOH (3 mL/3 mL/0.1 mL) was hydrogenated at RT under atmospheric pressure using a slurry solution of Raney nickel catalyst in water (0.5 mL) for 5 h. The catalyst was filtered off over Celite and the filtrate was concentrated, furnishing 160 mg of white solid (83% yield).

Step 3:

Saponification using standard methodology described in general method C.

Example 284: compound n^(o) 353: (2S,5R)-5-(2-chlorophenyl)-1-(3′-((E)-N′-hydroxycarbamimidoyl)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3′-((E)-N′-hydroxycarbamimidoyl)biphenylcarbonyl)pyrrolidine-2-carboxylate (step 1 of synthesis of compound n^(o) 352) using the saponification standard methodology described in general method C: (2S,5R)-1-(3′-carbamoyl-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was obtained by hydrolysis and saponification using LiOH of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3′-cyanobiphenylcarbonyl)pyrrolidine-2-carboxylate which was obtained from intermediate 1a and commercial 3′-cyanobiphenyl-4-carboxylic acid using general method C (conditions B).

Example 285: compound n^(o) 360: (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′,3′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2f4 using general method C (conditions B).

Example 286: compound n^(o) 361: (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-4′,5′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2g4 using general method C (conditions B).

Example 287: compound n^(o) 362: (2S,5R)-5-(2-chlorophenyl)-1-(3′,4′,5′-trimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2h4 using general method C (conditions B).

Example 288: compound n^(o) 363: (2S,5R)-5-(2-chlorophenyl)-1-(2′-(cyanomethyl)-4′,5′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2i4 using general method C (conditions B).

Example 289: compound n^(o) 364: (2S,5R)-5-(2-chlorophenyl)-1-(3′,4′-dicyano-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2j4 using general method C (conditions B).

Example 290: compound n^(o) 365: (2S,5R)-5-(2-chlorophenyl)-1-(5′-cyano-2′-fluoro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2k4 using general method C (conditions B).

Example 291: compound n^(o) 366: (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-3′,4′-dimethoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 214 using general method C (conditions B).

Example 292: compound n^(o) 367: (2S,5R)-5-(2-chlorophenyl)-1-(4-(2,6-dimethoxypyridin-3-yl)-3-fluorobenzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2m4 using general method C (conditions B).

Example 293: compound n^(o) 368: (2S,5R)-5-(2-chlorophenyl)-1-(3-fluoro-4-(6-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1a and 2n4 using general method C (conditions B).

Example 294: compound n^(o) 369: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-cyano-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the methodology shown in scheme 13.

Example 295: compound n^(o) 370: (2S,5R)-1-(1-(2-chloro-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized using the methodology shown in scheme 13 replacing 2-cyano-4-trifluoromethyl-bromobenzene with 2-chloro-4-trifluoromethyl-bromobenzene.

Example 296: compound n^(o) 371: (2S,5R)-1-(5′-cyano-T-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g and 2z3 using general method C (conditions B).

Example 297: compound n^(o) 372: (2S,5R)-1-(4-(2,6-dimethoxypyridin-3-yl)-3-fluorobenzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g and 2m4 using general method C (conditions B).

Example 298: compound n^(o) 373: (2S,5R)-1-(3-fluoro-4-(6-methoxypyridin-3-yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediates 1g and 2n4 using general method C (conditions B).

Example 299: compound n^(o) 374: (2S,5R)-1-(4-(3,6-dimethoxypyridazin-4-yl)benzoyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2r4 using general method C (conditions B).

Example 300: compound n^(o) 375: (2S,5R)-1-(3′-carbamoyl-4′-cyano-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was obtained by the hydrolysis of the nitrile moiety of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3′,4′-dicyano-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate and subsequent saponification using LiOH. (2S,5R)-methyl 5-(2-chlorophenyl)-1-(3′,4′-dicyano-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate was obtained from intermediates 1a and intermediate 2j4 using general method C (conditions B).

Example 302: compound n^(o) 376: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 303: compound n^(o) 377: (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-(morpholinosulfonyl)-2-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(2-nitro-4-(piperidin-1-ylsulfonyl)phenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 304: compound n^(o) 378: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-nitro-4-(piperidin-1-ylsulfonyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(4-(N,N-diethylsulfamoyl)-2-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 305: compound n^(o) 379: (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-(N,N-diethylsulfamoyl)-2-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(4-methyl-2-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 306: compound n^(o) 380: (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-methyl-2-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as depicted in scheme 12, replacing 2-nitro-4-trifluoromethyl-fluorobenzene by 2-nitro-4-methyl-fluorobenzene.

Example 307: compound n^(o) 381: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-cyano-4-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as depicted in scheme 12, replacing 2-nitro-4-trifluoromethyl-fluorobenzene by 2-cyano-4-methyl-fluorobenzene.

Example 308: compound n^(o) 382: (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(4-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 309: compound n^(o) 383: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-fluoro-4-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized using the same methodology as depicted in scheme 13, replacing 2-cyano-4-trifluoromethyl-bromobenzene by 2-fluoro-4-nitro-bromobenzene.

Example 310: compound n^(o) 384: (2S,5R)-5-(2-chlorophenyl)-1-(1-(3-methoxy-4-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(3-methoxy-4-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 311: compound n^(o) 385: (2S,5R)-1-(1-(5-chloro-2-nitrophenyl)piperidine-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(5-chloro-2-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 312: compound n^(o) 386: (2S,5R)-5-(2-cyanophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained by cyanation of (2S,5R)-methyl 5-(2-bromophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate and subsequent saponification. (2S,5R)-methyl 5-(2-bromophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate was obtained from intermediates 1i1 and 2h using general method C, (conditions A). Cyanation method of cyanation: In a carrousel tube were introduced NMP (0.2 mL), i-PrOH (9.7 μL), sodium carbonate (0.021 g, 0.202 mmol), palladium(II) acetate (0.908 mg, 4.05 μmol) and (2S,5R)-methyl 5-(2-bromophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate (0.1 g, 0.202 mmol). The RM was heated at 140° C. and potassium ferrocyanide.3H₂O (0.026 g, 0.061 mmol) was added. Heating was stopped and the RM was stirred overnight. The RM was diluted with water and extracted with three times with EtOAc. The aqueous layer was acidified (a color change from brown to blue was observed) and extracted twice with diethyl ether. The combined organic layers were dried over MgSO₄, filtered and concentrated to afford a brown residue. Crude was purified by flash chromatography (EtOAc/PE:1/2) to yield compound n^(o) 386. Y=10%, P>90%.

Example 313: compound n^(o) 387: (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-4′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2s4 using general method C (conditions B).

Example 314: compound n^(o) 388: (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-4′-(methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2s5 using general method C (conditions B).

Example 315: compound n^(o) 389: (2S,5R)-5-(2-chlorophenyl)-1-(2-fluoro-3′-(methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2t5 using general method C (conditions B).

Example 316: compound n^(o) 390: (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-2-fluoro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2u5 using general method C (conditions B).

Example 317: compound n^(o) 391: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-cyano-4-(methylsulfonamido)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained by reduction of nitro, sulfonylation and saponification of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(1-(2-cyano-4-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate which was obtained from intermediate 1a and commercial 1-(2-cyano-4-nitrophenyl)piperidine-4-carboxylic acid using general method C, condition B.

Example 318: compound n^(o) 392: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-cyano-4-methoxyphenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained using the same methodology as shown in scheme 13 replacing 2-cyano-4-trifluoromethyl-bromobenzene with 2-cyano-4-methoxy-bromobenzene.

Example 319: compound n^(o) 393: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-(methylsulfonamido)-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained by reduction of the nitro group of (2S,5R)-methyl 5-(2-chlorophenyl)-1-(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate, followed by sulfonylation with methane sulfonyl chloride, and subsequent saponification. (2S,5R)-methyl-5-(2-chlorophenyl)-1-(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylate was obtained from intermediates 1a and commercial 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 320: compound n^(o) 394: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-nitrophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(2-nitrophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 321: compound n^(o) 395: (2S,5R)-5-(2-chlorophenyl)-1-(1-(4-cyanophenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 1-(4-cyanophenyl)piperidine-4-carboxylic acid using general method C (conditions B).

Example 322: compound n^(o) 396: (2S,5R)-5-(3,5-difluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 111 and intermediate 2h using general method C (conditions A).

Example 323: compound n^(o) 397: (2S,5R)-5-(3,4-difluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1m1 and intermediate 2h using general method C (conditions A).

Example 324: compound n^(o) 398: (2S,5R)-5-(2,3-difluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1n1 and intermediate 2h using general method C (conditions A).

Example 325: compound n^(o) 399: (2S,5R)-5-(2,5-difluorophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 101 and intermediate 2h using general method C (conditions A).

Example 326: compound n^(o) 400: (2S,5R)-5-([1,1′-biphenyl]-2-yl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained by Suzuki coupling (2S,5R)-methyl 5-(2-bromophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate with phenylboronic acid and subsequent saponification. (2S,5R)-methyl 5-(2-bromophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylate was obtained from intermediates 1i1 and 2h using general method C (conditions A).

Example 327: compound n^(o) 401: (2S,5R)-1-(2′-cyano-4′-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1g and 2s4 using general method C (conditions B).

Example 328: compound n^(o) 402: (2S,5R)-5-(4-cyanophenyl)-1-(2′-methoxy-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1 μl and 2h using general method C (conditions A).

Example 329: compound n^(o) 403: (2S,5R)-5-(2-chlorophenyl)-1-(4-(5-methyl-4-(phenylsulfonyl)-1H-1,2,3-triazol-1-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthesized from intermediate 1a and commercial 4-(5-methyl-4-(phenylsulfonyl)-1H-1,2,3-triazol-1-yl)benzoic acid using general method C (conditions B).

Example 330: compound n^(o) 404: (2S,5R)-5-(2-chlorophenyl)-1-(3′-cyano-4′-fluoro-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2u4 using general method C (conditions B).

Example 331: compound n^(o) 405: (2S,5R)-1-(2′-chloro-5′-cyano-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2v4 using general method C (conditions B).

Example 332: compound n^(o) 406: (2S,5R)-5-(2-chlorophenyl)-1-(2′-cyano-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2w4 using general method C (conditions B).

Example 333: compound n^(o) 407: (2S,5R)-5-(2-chlorophenyl)-1-(1-(2-methoxy-4-(trifluoromethyl)phenyl)piperidine-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained using the same methodology as depicted in scheme 12, replacing 2-nitro-4-trifluoromethyl-fluorobenzene by 2-methoxy-4-trifluoromethyl-fluorobenzene.

Example 334: compound n^(o) 408: (2S,5R)-5-(2-chlorophenyl)-1-(2′-methyl-3′-(N-methylmethylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2x4 using general method C (conditions B).

Example 335: compound n^(o) 409: (2S,5R)-5-(2-chlorophenyl)-1-(2′-methoxy-4′-(N-methylmethylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2v5 using general method C (conditions B).

Example 336: compound n^(o) 410: (2S,5R)-5-(2-chlorophenyl)-1-(6-(5-cyano-2-methoxyphenyl)-5-methoxynicotinoyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2y4 using general method C (conditions B).

Example 337: compound n^(o) 411: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2,4-dimethoxyphenyl)-5-methoxynicotinoyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2z4 using general method C (conditions B).

Example 338: compound n^(o) 412: (2S,5R)-5-(2-chlorophenyl)-1-(6-(2,4-dimethoxyphenyl)nicotinoyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1a and intermediate 2a5 using general method C (conditions B).

Example 339: compound n^(o) 413: (2S,5R)-1-(2′-cyano-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1g and intermediate 2w4 using general method C (conditions B).

Example 340: compound n^(o) 414: (2S,5R)-1-(3′-cyano-4′-fluoro-[1,1′-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1g and intermediate 2u4 using general method C (conditions B).

Example 341: compound n^(o) 415: (2S,5R)-1-(2′-chloro-5′-cyano-[1,1′-biphenyl]-4-carbonyl)-5-(2-fluorophenyl)pyrrolidine-2-carboxylic acid was obtained from intermediates 1g and intermediate 2v4 using general method C (conditions B).

Example 342: compound n^(o) 416: (2S,5R)-5-(2-chlorophenyl)-1-(4-(3,6-dimethoxypyridazin-4-yl)-3-fluorobenzoyl)pyrrolidine-2-carboxylic acid was synthetized from 1a and 2w5 using general method C (conditions B).

Example 343: compound n^(o) 417: (2S,5R)-5-(2-fluorophenyl)-1-(2′-methyl-3′-(N-methylmethylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates 1g and 2x4 using general method C (conditions B).

Example 344: compound n^(o) 418: (2S,5R)-5-(2-fluorophenyl)-1-(2′-methoxy-4′-(N-methylmethylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthetized from 1 g and 2v5 using general method C (conditions B).

Example 345: compound n^(o) 419: (2S,5R)-5-(2-chlorophenyl)-1-(4-(4,6-dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthetized from 1a and 2f5 using general method C (conditions B).

Example 346: compound n^(o) 420: (2S,5R)-5-(2,3-difluorophenyl)-1-(4-(2,4-dimethoxypyrimidin-5-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates 1n1 and 2s1 using general method C (conditions B).

Example 347: compound n^(o) 421: (2S,5R)-1-(5′-cyano-2′-methyl-[1,1′-biphenyl]-4-carbonyl)-5-(2,3-difluorophenyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates 1n1 and 2a4 using general method C (conditions B).

Example 348: compound n^(o) 354: (2S,5R)-5-(2-fluorophenyl)-1-(2′-methoxy-4′-(methylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates 1g and 2p5 using general method C (conditions B).

Example 349: compound n^(o) 355: (2S,5R)-5-(2,4-difluorophenyl)-1-(4-(2,6-dimethoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates 1k1 and 2q5 using general method C (conditions B).

Example 350: compound n^(o) 356: (2S,5R)-5-(2-chlorophenyl)-1-(3-methoxy-4-(5-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates 1a and 2d4 using general method C (conditions B).

Example 351: compound n^(o) 357: (2S,5R)-1-(4′-amino-2′-methoxy-[1,1′-biphenyl]-4-carbonyl)-5-(2-chlorophenyl)pyrrolidine-2-carboxylic acid was synthetized from intermediate 1a and methyl 2′-methoxy-4′-amino-[1,1′-biphenyl]-4-carboxylate obtained in the synthesis of intermediate 2p5.

Example 352: compound n^(o) 358: (2S,5R)-5-(2-chlorophenyl)-1-(2′,3,6′-trimethoxy-[2,3′-bipyridine]-5-carbonyl)pyrrolidine-2-carboxylic acid was synthetized from intermediates 1a and 2e4 using general method C (conditions B).

Biology Examples

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents the effect of compounds 1; 2; 4; 5; 8; 10; 11 and 13 on isoprenaline-induced lipolysis in adipocytes isolated from normal rat. Compounds are tested at 30 μM final concentration.

FIGS. 2A and 2B represent the inhibition of blood glucose concentration in OGTT assay following bi-daily injection (at 50 mg/kg) of compound 1 during 28 days.

Membrane Binding Assay: GTPγS Binding Assay

The following assay can be used for determination of GPR43 activation. When a GPCR is in its active state, either as a result of ligand binding or constitutive activation, the receptor couples to a G protein and stimulates the release of GDP and subsequent binding of GTP to the G protein. The alpha subunit of the G protein-receptor complex acts as a GTPase and slowly hydrolyses the GTP to GDP, at which point the receptor normally is deactivated. Activated receptors continue to exchange GDP for GTP. The non-hydrolysable GTP analog, [³⁵S]GTPγS, was used to demonstrate enhance binding of [³⁵S]GTPγS to membranes expressing receptors. The assay uses the ability of GPCR to stimulate [³⁵S]GTPγS binding to membranes expressing the relevant receptors. The assay can, therefore, be used in the direct identification method to screen candidate compounds to endogenous or not endogenous GPCR.

Preparation of Membrane Extracts:

Membrane extracts were prepared from cells expressing the human GPR43 receptor (hGPR43) as follows: the medium was aspirated and the cells were scraped from the plates in Ca⁻⁺ and Mg⁺⁻-free Phosphate-buffered saline (PBS). The cells were then centrifuged for 3 min at 1500 g and the pellets were resuspended in buffer A (15 mM Tris-HCl pH 7.5, 2 mM MgCl₂, 0.3 mM EDTA, 1 mM EGTA) and homogenized in a glass homogenizer. The crude membrane fraction was collected by two consecutive centrifugation steps at 40.000×g for 25 min separated by a washing step in buffer A. The final pellet was resuspended in 500 μl of buffer B (75 mM Tris-HCl pH 7.5, 12.5 mM MgCl₂, 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose) and flash frozen in liquid nitrogen. Protein content was assayed by the Folin method.

GTPγS Assay (SPA Method):

The assay was used to determine the activity of the compounds of the invention. The [³⁵S]GTPγS assay was incubated in 20 mM HEPES pH7.4, 100 mM NaCl, 10 μg/ml saponin, 30 mM of MgCl₂, 10 μM of GDP, 5 μg membrane-expressing hGPR43, 250 μg of wheat germ agglutinin beads (Amersham, ref: RPNQ001), a range concentration of compounds of the invention (from 30 μM to 1 nM) in a final volume of 100 μl for 30 min at room temperature. The SCFA propionate was used at 1 mM final concentration as positive control. The plates were then centrifuged for 10 minutes at 2000 rpm, incubated for 2 hours at room temperature and counted for 1 min in a scintillation counter (TopCount, PerkinElmer). The results of the tested compounds are reported as the concentration of the compound required to reach 50% (EC₅₀) of the maximum level of the activation induced by these compounds.

When tested in the assay described above and by way of illustration the compounds in Table 3 activate GPR43 receptor. The EC₅₀ value obtained is represented as follows: “+++” means EC₅₀<200 nM; “++” means 200 nM≤EC₅₀≤1 μM; “+” means EC₅₀>1 μM.

TABLE 3 Compounds EC₅₀ values in GTPγ³⁵S assay. Compound no EC₅₀ (nM) 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 8 ++ 9 ++ 10 ++ 11 ++ 12 ++ 13 ++ 14 ++ 15 ++ 16 ++ 17 ++ 18 ++ 19 ++ 20 ++ 21 ++ 23 + 24 + 26 + 27 + 30 + 31 + 32 + 33 + 34 + 35 + 36 + 38 + 39 + 40 + 41 + 42 + 43 + 44 + 45 + 47 + 48 + 49 + 52 + 53 + 58 + 59 + 77 +++ 78 ++ 83 + 88 + 89 ++ 91 ++ 96 ++ 99 ++ 102 + 105 + 107 + 108 + 109 + 113 +++ 114 + 116 ++ 117 ++ 120 + 121 ++ 122 +++ 123 +++ 125 ++ 126 +++ 127 +++ 128 +++ 129 +++ 130 +++ 131 + 132 +++ 133 ++ 134 ++ 135 +++ 136 ++ 137 ++ 138 +++ 140 +++ 141 ++ 143 + 149 ++ 150 ++ 151 ++ 153 + 155 + 156 ++ 157 +++ 160 ++ 161 +++ 162 + 169 + 174 + 176 + 177 + 178 ++ 179 + 183 + 184 ++ 189 ++ 191 ++ 192 ++ 193 +++ 194 ++ 195 ++ 196 +++ 197 +++ 198 +++ 199 +++ 200 +++ 201 +++ 202 +++ 203 ++ 204 +++ 206 + 207 + 224 +++ 225 +++ 226 ++ 227 +++ 228 +++ 229 +++ 230 + 231 + 232 +++ 233 ++ 234 + 235 +++ 236 +++ 237 ++ 239 ++ 240 ++ 242 ++ 246 +++ 247 +++ 261 ++ 268 +++ 269 +++ 272 ++ 273 ++ 274 ++ 275 +++ 276 ++ 278 ++ 279 + 280 + 281 ++ 283 +++ 284 ++ 285 + 286 + 287 ++ 288 ++ 289 +++ 290 +++ 291 ++ 292 +++ 293 ++ 294 ++ 295 + 296 + 297 +++ 298 +++ 299 +++ 300 ++ 301 ++ 302 +++ 303 ++ 304 + 305 + 306 + 307 +++ 308 +++ 309 ++ 310 ++ 311 +++ 312 +++ 313 ++ 314 +++ 315 +++ 316 +++ 318 + 319 ++ 320 +++ 321 ++ 322 ++ 323 ++ 324 ++ 325 +++ 326 + 327 ++ 328 +++ 329 ++ 330 ++ 331 ++ 332 + 333 + 334 ++ 335 + 336 + 337 +++ 338 +++ 339 ++ 340 +++ 341 + 342 +++ 343 +++ 344 ++ 345 +++ 346 +++ 347 +++ 348 +++ 349 ++ 350 +++ 351 +++ 352 + 353 ++ 354 +++ 355 +++ 356 +++ 357 +++ 358 ++ 359 ++ 360 +++ 361 +++ 362 +++ 363 ++ 364 + 365 ++ 366 +++ 367 +++ 368 +++ 369 ++ 370 + 371 +++ 372 +++ 373 ++ 374 ++ 375 ++ 386 ++ 387 +++ 388 +++ 389 +++ 390 +++ 391 + 392 + 393 + 395 ++ 396 ++ 397 ++ 398 +++ 399 +++ 400 ++ 401 +++ 402 + 403 + 404 ++ 405 +++ 406 +++ 407 ++ 408 +++ 409 +++ 410 ++ 411 ++ 412 ++ 413 +++ 414 + 415 +++ 416 +++ 417 +++ 418 ++ 419 +++ 420 +++ 421 +++ Radioligand Binding (RLB) Assay with Cell Membrane Extracts from Human GPR43 Recombinant Cell Line

Human GPR43 radioligand binding assay is performed by adding successively in the wells of a 96 well plate (Master Block, Greiner, 786201), 50 μl of compound of the invention at increasing concentrations (diluted in assay buffer: 50 mM Tris pH 7.4), 25 μl radiolabeled antagonist (ie. compound n^(o) 277 described in EP10305100.9) diluted in assay buffer and 25 μl cell membrane extracts (10 protein/well). The final concentration of radiolabeled antagonist in the assay is 10 nM. The plate is incubated 60 min at 25° C. in a water bath and then filtered over GF/B filters (Perkin Elmer, 6005177, presoaked in 0.05% Brij for 2 h at room temperature) with a Filtration unit (Perkin Elmer). The filters are washed 3 times with 0.5 ml of ice-cold wash buffer (50 mM Tris pH 7.4). 50 μl of Microscint 20 (Packard), is added and the plate is incubated 15 min on an orbital shaker and then counted with a TopCount™ for 1 min/well.

In Table 4 biological results obtained using the RLB assay as described above with compounds of the invention are set out in tabulated form. In this table, the constant of inhibition of radioligand binding carried out by the compound of the invention (Ki) is given. The Ki values (nM) obtained is represented as follows: “+++” means Ki<1 μM; “++” means 1 μM≤Ki≤2 μM; “+” means 2 μM<Ki.

TABLE 4 Compounds Ki values in RLB assay. Compound no Ki (nM) 376 +++ 377 + 378 ++ 379 + 380 ++ 381 ++ 382 + 383 + 384 + 385 +++ 394 + Cell Based Assay: Calcium Flux. The Aequorin-Based Assay.

The following assay can be used for determination of GPR43 activation. The aequorin assay uses the responsiveness of mitochondrial apoaequorin to intracellular calcium release induced by the activation of GPCRs (Stables et al., 1997, Anal. Biochem. 252:115-126; Detheux et al., 2000, J. Exp. Med., 192 1501-1508). Briefly, GPCR-expressing clones are transfected to coexpress mitochondrial apoaequorin and Gα16. Cells expressing GPR43 receptor are incubated with 5 μM Coelenterazine FI (Molecular Probes) for 4 hours at room temperature, washed in DMEM-F12 culture medium and resuspended at a concentration of 0.5×10⁶ cells/ml (the amount can be changed for optimization). Cells are then mixed with test compounds and light emission by the aequorin is recorded with a luminometer for 30 sec. Results are expressed as Relative Light Units (RLU). Controls include assays using cells not expressing GPR43 (mock transfected), in order to exclude possible non-specific effects of the candidate compound.

Aequorin activity or intracellular calcium levels are “changed” if light intensity increases or decreases by 10% or more in a sample of cells, expressing a GPR43 and treated with a compound of the invention, relative to a sample of cells expressing the GPR43 but not treated with the compound of the invention or relative to a sample of cells not expressing the GPR43 (mock-transfected cells) but treated with the compound of the invention.

Cell Based Assay: Intracellular Inositol-Phosphate Accumulation Assay. (Gq-Associated Receptor)

The following assay can be used for determination of GPR43 activation. On day 1, GPR43-expressing cells in mid-log phase are detached with PBS-EDTA, centrifuged at 2000×g for 2 min and resuspended in medium without antibiotics. After counting, cells are resuspended at 4×10⁵ cells/ml (the amount can be changed for optimization) in medium without antibiotics, distributed in a 96 well plate (100 μl/well) and the plate is incubated overnight at 37° C. with 5% CO₂. On day 2, the medium is removed and the compounds of the invention, at increasing concentrations, are added (24 μl/well) and the plate is incubated for 30 min. at 37° C. in a humidified atmosphere of 95% air with 5% CO₂. The IP1 concentrations are then estimated using the IP1-HTRF assay kit (Cisbio international, France) following the manufacturer recommendations.

Cell Based Assay: cAMP Accumulation Assay (G_(i/o) Associated Receptor)

The following assay can be used for determination of GPR43 activation. Cells expressing GPR43 in mid-log phase and grown in media without antibiotics are detached with PBS-EDTA, centrifuged and resuspended in media without antibiotics. Cells are counted and resuspended in assay buffer at 4.2×10⁵ cells/ml. 96 well plates are filled with 12 μl of cells (5×10³ cells/well), 6 μl of compound of the invention at increasing concentrations and 6 μl of Forskolin (final concentration of 10 μM). The plate is then incubated for 30 min. at room temperature. After addition of the lysis buffer, cAMP concentrations are estimated, according to the manufacturer specification, with the HTRF kit from Cis-Bio International.

In Vitro Assays to Assess Compound Activity in 3T3-L1 Cell Line.

3T3-L1 adipocytes cell line has been described as cellular model to assess compounds mimicking insulin-mediated effect such as inhibition of lipolysis and activation of glucose uptake.

Lipolysis.

3T3-L1 cells (ATCC) are cultured in Dulbecco's modified eagle's medium (DMEM) containing 10% (v/v) bovine serum (fresh regular medium) in 24 well plate. On day 0 (2 days after 3T3-L1 preadipocytes reached confluence), cells are induced to differentiate by insulin (10 μg/ml), IBMX (0.5 mM) and dexamethasone (1 μM). On day 3 and every other 3^(rd) day thereafter, fresh regular medium is substituted until day 14.

On day 14, the medium is removed and cells are washed twice with 1 ml of a wash buffer (Hank's balanced salt solution). The wash solution is removed and the SCFA or the tested compounds, or a combination of both, are added at the desired concentration in Hank's buffer supplemented with 2% BSA-FAF and incubated for 10 minutes a 37° C. Then, isoproterenol (100 nM) is added to induce lipolysis and incubate for 30 minutes at 37° C. The supernatants are collected in a glycerol-free container. 25 μl (the amount can be changed for optimization) of cell-free supernatants are dispensed in 96-well microtiter plate, 25 μl of free glycerol assay reagent (Chemicon, the amount can be changed for optimization) is added in each well and the assay plate is incubated for 15 minutes at room temperature. The absorbance is recorded with a spectrophotometer at 540 or 560 nm. Using the supernatants, the free fatty acids amount can be assessed using the NEFA assay kit (Wako) according the manufacturer's recommendations.

Glucose Uptake.

3T3-L1 cells are differentiated as described previously with or without of 30 μM of tested compounds (the concentration can be changed for optimization) during the 14 days of differentiation. The day of the experiment, the cells are washed twice with a KREBS-Ringer bicarbonate (pH 7.3) supplemented with 2 mM sodium pyruvate and starved for 30 minutes in the same buffer at 37° C. in an atmosphere containing 5% CO2 and 95% 02. Various amount of SCFA, tested compounds or combination of both are then added with or without 10 nM of insulin (the amount can be changed for optimization) for 30 minutes at 37° C. in an atmosphere containing 5% CO2 and 95% O2. Then, D-(³H)-2 deoxyglucose (0.2 μCi/well) and D-2-deoxyglucose (0.1 mM) is added for 30 minutes. To stop the reaction, the cells are immersed in ice-cold saline buffer, washed for 30 min, and then dissolved in NaOH 1M at 55° C. for 60 minutes. NaOH is neutralized with HCl 1M. The 3H labeled radioactivity of an aliquot of the extract is counted in the presence of a scintillation buffer.

In Vitro Assays to Assess Compound Activity in NCI-H716 Cell Line.

Human intestinal cell line NCI-H716 has been described as cellular model to assess compounds mimicking nutrient-mediated effect such as glucagon-like peptide-1 (GLP-1) secretion.

GLP-1 Release.

NCI-H716 cells (ATCC, Manassas) are cultured in Dulbecco's modified eagle's medium (DMEM) containing 10% (v/v) bovine serum, 2 mM L-glutamine, 100 IU/ml penicillin and 100 μg/ml streptomycin in 75 ml flask. Cell adhesion and endocrine differentiation is initiated by growing cells in 96-well plate coated with matrigel in High Glucose DMEM containing 10% (v/v) bovine serum, 2 mM L-glutamine, 100 IU/ml penicillin and 100 μg/ml streptomycin for 2 days. On day 2, the medium is removed and cells are washed once with a pre-warmed wash buffer (Phosphate Buffered salt solution). The wash solution is removed and the SCFA or the tested compounds, or a combination of both, are added at the desired concentration in High Glucose DMEM containing 0.1% (v/v) bovine serum and incubated for 2 hours at 37° C. The supernatants are collected in a container. Using the cell-free supernatants, the GLP-1 amount is assessed using a GLP-1 specific ELISA assay kit according the manufacturer's recommendations (ALPCON).

Ex Vivo Assays to Assess Compound Activity in Adipocytes from Normal Rat or Mice and High-Fat Diet Fed Mice.

Mice C56Black6 male are housed in Makrolon type IV group housing cages (56×35×20 cm³) throughout the experimental phase. Animals' cages litters are changed once a week. They are housed in groups of 10 animals at 12 light dark (at 8 h30 pm lights off), 22+/−2° C. and 50+/−5% relative humidity. Animals are acclimated one week. During the whole phase, standard diet or diet high in energy from fat (Research Diets, New Brunswick, N.J.) and tap water are provided ad libitum. The animals are 16 weeks old at the time of the study.

For keeping only mice that have responded to the high fat diet, fasted glycemia are measured in these mice just before performing the ex-vivo study.

Glucose Uptake Assay in Isolated Adipocytes.

Animals are killed by cervical dislocation and epididymal fat pads are removed and digested in collagenase buffer at 37° C./120 rpm for approximately 50 minutes. The digest is filtered through gauze to recover the adipocytes, which are washed and resuspended in Krebs-Ringer Hepes (KRH) buffer containing 1% BSA, 200 nM adenosine and 2 mM glucose.

Isolated adipocytes are washed in glucose-free KRH-buffer and resuspended to 30%. Adipocytes are then incubated at 37° C./80 rpm with either the tested compound (30 μM, 10 μM and 1 μM) in the presence or absence of insulin (10 nM) for 30 min 2-deoxyglucose and 2-deoxy-D-[1-³H]-glucose (³H-2-DOG) are added and incubation continued for 10 min. The reactions are then stopped by addition of cytochalasin b followed by centrifugation through dinonylphthalate to recover the adipocytes. The uptake of ³H-2-DOG- was measured by scintillation. Each data point is investigated in triplicates in two independent experiments.

Lipolysis Assay in Isolated Adipocytes.

Isolated adipocytes are diluted to 5% in KRH-buffer and are pre-treated with the tested compound (30 μM, 10 μM and 10 μM) for 30 min at 37° C./120 rpm. After the pre-treatment, Isoprenaline (1 μM) is added to the adipocytes followed by 30 min incubation at 37° C./150 rpm. The reactions are put on ice and the buffer is assayed spectrophotometrically for the production of NADH⁺ from glycerol breakdown in reactions catalyzed by glycerol kinase and glycerol-3-phosphate dehydrogenase and/or Non Esterified Fatty Acid (NEFA). Each data point is investigated in triplicates in two independent experiments.

According to the method described above and by way of illustration the compounds n° 1; 2; 4; 5; 8; 10; 11 and 13 inhibit isoprenaline-induced lipolysis in adipocytes from normal rat, at the concentration of 30 μM (FIG. 1).

In Vivo Assay to Assess Compound Activity in Rodent Diabetes Model.

Genetic Rodent Models:

Rodent models of T2D associated with obesity and insulin resistance have been developed. Genetic models such as db/db and ob/ob in mice and fa/fa in Zucker rats have been developed for understanding the pathophysiology of disease and testing candidate therapeutic compounds. The homozygous animals, C57 Black/6-db/db mice developed by Jackson Laboratory are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J Clin Invest, 1990, 85:962-967), whereas heterozygotes are lean and normoglycemic. In the db/db model, mice progressively develop insulinopenia with age, a feature commonly observed in late stages of human T2D when sugar levels are insufficiently controlled. Since this model resembles that of human T2D, the compounds are tested for activities including, but not limited to, lowering of plasma glucose and triglycerides. Zucker (fa/fa) rats are severely obese, hyperinsulinemic, and insulin resistant, and the fa/fa mutation may be the rat equivalent of the murine db mutation.

Genetically altered obese diabetic mice (db/db) (male, 7-9 weeks old) are housed under standard laboratory conditions at 22° C. and 50% relative humidity, and maintained on a diet of Purina rodent chow and water ad libitum. Prior to treatment, blood is collected from the tail vein of each animal and blood glucose concentrations are determined using one touch basic glucose monitor system (Lifescan). Mice that have plasma glucose levels between 250 to 500 mg/dl are used. Each treatment group consists of several mice that are distributed so that the mean of glucose levels are equivalent in each group at the start of the study. Db/db mice are dosed by micro-osmotic pumps, inserted using isoflurane anesthesia, to provide compounds of the invention, saline, or an irrelevant compound to the mice intravenously (i.v). Blood is sampled from the tail vein at intervals thereafter and analyzed for blood glucose concentrations. Significant differences between groups (comparing compounds of the invention to saline-treated) are evaluated using Student t-test.

Ob/ob or obese mice are leptin-deficient mice that eat excessively and become profoundly obese, hyperinsulinemic and hyperglycemic. It is an animal model of type II diabetes. Such model can be used for oral glucose tolerance tests (OGTTs). A total of sixteen (16) male ob/ob mice (6 weeks of age) were obtained from Harlan. Upon arrival to the animal unit, mice were housed 4 per cage in rodent cages mounted with feeders containing regular chow. The mice were put in a 12/12 h light-dark cycle (light from 0600-1800 h) with controlled temperature conditions (22-24° C.). Fed blood glucose and body-weight was measured on day −2 in the morning between 08:00 AM and 09:00 AM. Animals were randomized into 2 groups according to fed glucose levels (on day −2). The 16 mice with blood glucose and body-weight closest to the mean were distributed into the following groups: Group 1: Vehicle p.o. bi-daily, (n=8) and Group 2: Compound of the invention, p.o., bi-daily, (n=8).

Day 1 is the first day of dosing. Animals were dosed with compounds of the invention at 07:00 AM and 04:00 PM for 28 days. On the evening of day 27, food was removed and mice were transferred to clean cages. Mice were fasted for the subsequent 17 hours until the OGTT was performed. At −15 min, blood glucose was measured (using a glucose analyzer) and animals were dosed with compounds of the invention or vehicle. At time point 0, blood glucose was measured again and glucose was administered by oral gavage (lg/kg glucose). The blood glucose was then measured at time points 15, 30, 45, 60 and 120 minutes. The blood glucose area under the curve (AUC) from time −15 to 120 min was then calculated (GraphPad software). The percentages of AUC inhibition induced by compounds of the invention were calculated as follows: % of AUC inhibition: [1−(AUC compound/AUC vehicule)]*100.

When tested in the above-described assay, the compound 1 showed a % of AUC inhibition of 40%, indicating that compound 1 is able to significantly reduce the level of blood glucose in diabetic animal model (FIGS. 2A and 2B).

The High-Fat Diet Fed Mouse:

This model was originally introduced by Surwit et al. in 1988. The model has shown to be accompanied by insulin resistance, as determined by intravenous glucose tolerance tests, and of insufficient islet compensation to the insulin resistance. The model has, accordingly, been used in studies on pathophysiology of impaired glucose tolerance (IGT) and type 2 diabetes and for development of new treatments.

C57BL/6J mice are maintained in a temperature-controlled room (22° C.) on a 12-h light-dark cycle. One week after arrival, mice are divided into two groups and are fed either a high-fat diet or received continuous feeding of a normal diet for up to 12 months. On caloric basis, the high-fat diet consist of 58% fat from lard, 25.6% carbohydrate, and 16.4% protein (total 23.4 kJ/g), whereas the normal diet contains 11.4% fat, 62.8% carbohydrate, and 25.8% protein (total 12.6 kJ/g). Food intake and body weight are measured once a week, and blood samples are taken at indicated time points from the intraorbital retrobulbar plexus from nonfasted anesthetized mice.

For intravenous glucose tolerance tests (IVGTTs), 4-h fasted mice are anesthetized with 7.2 mg/kg fluanison/fenlanyl and 15.3 mg/kg midazolam. Thereafter a blood sample is taken from the retrobulbar, intraorbital, capillary plexus, after which D-glucose (1 g/kg) is injected intravenously in a tail vein (volume load 10 l/g). Additional blood samples are taken at 1, 5, 10, 20, 50, and 75 min after injection. Following immediate centrifugation at 4 C, plasma is separated and stored at −20 C until analysis. For oral glucose tolerance tests (OGTTs), 16-h fasted anesthetized mice are given 150 mg glucose by gavage through a gastric tube (outer diameter 1.2 mm), which is inserted in the stomach. Blood samples are taken at 0, 15, 30, 60, 90, and 120 min after glucose administration and handled as above.

Administration of the compounds: Five-week-old mice are fed a high-fat or a normal diet for 8 weeks. After 4 weeks, the mice are additionally given the compound of the invention in their drinking water (0.3 mg/ml, the amount can be changed for optimization. Control groups are given tap water without compound.

After another 4 weeks, the mice are subjected to an OGTT as described above. Insulin and glucose measurements: Insulin is determined enzymatically using an ELISA assay kit (Linco Research, St. Charles, Mo.). Plasma glucose is determined by the glucose oxidase method.

In Vivo Assay to Assess Compound Anti-Obesity Activity in Rodent Model.

Mouse Acute Food Intake and Weight Change:

Male C57BL/6N wild-type mice are weighed and vehicle or the tested compounds are administered by oral gavage to male mice approximately 30 min prior to the onset of the dark phase of the light cycle. Mice are fed ad libitum in the dark phase following dosing. A preweighed aliquot of a highly palatable medium high fat diet is provided in the food hopper of the cage 5 min prior to the onset of the dark phase of the light cycle and weighed 2 and 18 h after the onset of the dark phase of the light cycle.

Acute Studies in Diet-Induced Obesity (DIO) Rats:

For acute experiments, male Sprague-Dawley DIO rats from Charles River Laboratories are raised from 4 weeks of age on a diet moderately high fat (32% kcal) and high in sucrose (25% kcal). Animals are used at 12 weeks of age and are maintained on a 12/12 h light dark cycle. The rats are randomized into groups (n=6/group) for the tested compounds and vehicle dosing. Rats are weighed 17 h after dosing to determine effects on overnight body weight gain. The tested compounds are administered orally or s.c. at amount desired 1 h before the start of the dark cycle. Powdered food is provided in food cups which are weighed continuously at 5 min intervals over 18 h and the data are recorded using a computerized system.

Chronic Studies in Diet-Induced Obesity Rats:

For the 14-day chronic experiment, male Sprague-Dawley DIO rats are obtained as described above. Animals are used at 15 weeks of age and are maintained on a 12/12 hour light-dark cycle. Rats are conditioned to dosing for 4 days prior to baseline measurements, using an oral gavage or a s.c. route of vehicle. Thereafter, animals are dosed daily with vehicle or compound by oral gavage or s.c. The tested compound or vehicle is administered 1 h before the dark cycle for 14 days. Body composition is measured by dual energy X-ray densitometry (DEXAscan) 5 days prior to the study and at the end of the 14-day study. Daily endpoints included body weight and food intake.

In Vivo Assay to Assess Compound Anti-Lipolytic Activity in Rodent Model.

Male C57BL/6N wild-type are housed one per cage in a room maintained on a 12 h light/dark cycle under constant temperature (22-25° C.) with ad libitum access to food and water. The anti-lipolytic effects of the tested compounds are studied in awake mice. Animals are fasted overnight before experimental use. On the day of the experiment, animals are put in metabolic cages and left undisturbed to acclimate to the environment for 1-2 h. blood samples are taken at indicated time points from the intraorbital retrobulbar plexus. A 1% sodium citrate saline solution is used to flush the lines. A pre-treatment blood sample is obtained from each animal to determine baseline values for free fatty acids (FFA) and triglycerides (TG). The tested compounds are given via oral gavage, sc injection, iv injection or ip injection for each different series of experiments. Blood samples are collected into pre-cooled tubes pre-coated with heparin (200 μl blood, Li-heparin, Sarstedt) for determination triglycerides and glycerol and in tri-potassium EDTA added sodium fluoride (200 μl blood, K₃-EDTA, 1.6 mg/mL+1% NaF, Sarstedt) for determination of plasma free fatty acids. The tubes are placed on wet ice pending processing. Blood samples will be centrifuged at 4000×g, at 4° C., 15 min the resulting plasma will be transferred into non-coated tubes and stored at −80° C. until analyses. The plasma is thawed at 4° C. for determinations of FFA and TG using commercial kits (Wako Chemicals).

While embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation ant it is understood that various changes may be made without departing from the spirit and scope of the invention. 

The invention claimed is:
 1. A compound of formula E:

wherein: R is methyl, ethyl, benzyl, allyl, phenacyl, methoxymethyl, methylthiomethyl, 2-(methoxyethoxy)methyl, 2-(trimethylsilyl)ethyl, or tert-butyldiphenylsilyl; and (i) R⁸ is —Cl; and R⁹ is —H; or (ii) R⁸ is —F; and R⁹ is —H; or (iii) R⁸ is —F; and R⁹ is —F. 